- Email: [email protected]
A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer
Annals of Oncology 13: 1220–1224, 2002 DOI: 10.1093/annonc/mdf199
Original article
A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer K. D. Miller1*, W. Gradishar2, L. Schuchter3, J. A. Sparano4, M. Cobleigh5, N. Robert6, H. Rasmussen7 & G. W. Sledge1 1
Indiana University, Indianapolis, IN; 2Northwestern University, Chicago, IL; 3University of Pennsylvania, Philadelphia, PA; 4Montefiore Medical Center, New York, NY; 5Rush-Presbyterian Medical Center, Chicago, IL; 6Fairfax Hospital, Fairfax, VA; 7British Biotech, Annapolis, MD, USA
Received 26 September 2001; revised 10 December 2001; accepted 9 January 2002
Background: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. Patients and methods: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. Results: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40–200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. Conclusions: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range. Key words: angiogenesis, breast cancer, metalloproteinase, metalloproteinase inhibitor
Introduction
as the dose-limiting toxicity with biologically active levels achieved in patients with advanced malignancy with doses ranging from 5 to 10 mg b.i.d. Matrix metalloproteinase inhibitors significantly curtail primary tumor growth and establishment of metastases in several pre-clinical minimal disease models but fail to shrink large, well established tumors [9, 10]. As such, the most successful clinical application of MMP inhibitors such as marimastat is likely to be in patients with micrometastatic disease. Use in the adjuvant setting requires evidence that drug levels can be maintained above a minimal trough level chronically and safely. This pilot trial was designed to provide such evidence, as a necessary prelude to the appropriate proof of concept adjuvant trials.
The matrix metalloproteinase (MMP) family of enzymes degrade molecules of the basement membrane and extracellular matrix [1]. Under normal physiological conditions the MMPs and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), exist in an exquisite balance. Unbalanced MMP/TIMP expression plays a critical role in cellular movement, invasion, angiogenesis and metastasis [2–7]. Inhibition of the MMPs thus provides a potentially fruitful therapeutic target. Marimastat is a low molecular weight peptide mimetic containing a hydroxamate group that chelates the zinc atom of the active site of the MMPs. Marimastat inhibits a broad spectrum of MMPs and has activity in multiple human tumor xenograft models [8]. Phase I trials identified musculoskeletal syndromes including arthralgia/arthritis, tendonitis and bursitis
Patients and methods
*Correspondence to: Dr K. D. Miller, Division of Hematology/ Oncology, Indiana Cancer Pavilion, 535 Barnhill Drive, RT-473, Indianapolis, IN 46202, USA. Tel: +1-317-274-0920; Fax: +1-317-274-3646; E-mail: [email protected]
Patients with histologically confirmed high-risk node-negative (estrogen receptor-negative primary tumor >1 cm or estrogen receptor-positive tumor >2 cm) or node-positive breast cancer were eligible. All patients had undergone surgical excision of the primary tumor and completed radiation therapy if indicated. All patients were entered within 3 months of completing chemotherapy or initiating tamoxifen treatment. Patients had
© 2002 European Society for Medical Oncology
1221 Table 1. Patient characteristics Marimastat
Median age [years (range)]
5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
44 (33–58)
52 (41–75)
45 (34–65)
55 (43–72)
Stage at diagnosis I
0
4
4
2
II
6
19
6
15
III
0
0
1
1
Unknown
2
1
0
2
Caucasian
5
23
9
19
African–American
1
0
2
0
Asian
0
1
0
0
Hispanic
2
0
0
1
Ethnicity
to have adequate renal, hepatic, hematological and cardiac function. Each local institutional review board reviewed the protocol and individual written informed consent was provided prior to treatment. After eligibility was confirmed, patients were stratified according to planned tamoxifen therapy, age, stage, study site and then randomized to one of two doses of marimastat, either 5 or 10 mg b.i.d. for 12 months. Stratum A enrolled patients receiving adjuvant chemotherapy with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles. Stratum B enrolled patients receiving adjuvant hormonal therapy with tamoxifen 10 mg b.i.d.; patients enrolled in stratum B could have received adjuvant chemotherapy before initiating tamoxifen. Upon completion of the initial 12-month treatment period, patients could elect to continue marimastat therapy for a maximum of 5 years; patients continuing therapy beyond 12 months were evaluated every 3 months. Dose modifications were specified for musculoskeletal toxicity. Interruption of marimastat therapy was mandated for patients with bone, joint or muscle pain restricting activity [common toxicity criteria (CTC) grade ≥2]. Treatment was re-instituted at a once daily dosage (i.e. either 5 or 10 mg daily) once symptoms had subsided. If musculoskeletal symptoms recurred, treatment was discontinued until resolution and then restarted at either 5 or 10 mg every other day. Patients were evaluated monthly for the first 3 months then every 3 months while on study. Plasma samples for steady-state marimastat levels were obtained weekly during the first month, monthly for 2 months and then every 3 months for the first year of therapy; pharmacokinetic samples were not obtained when therapy was interrupted for toxicity. Plasma marimastat concentration was analyzed by a validated liquid chromatography–mass spectrometry procedure. The chromatographic system consisted of Novapak C18 analytical column (Waters Chromatography, Elstree, Hertfordshire, UK) and a mobile phase of methanol/water (55%/45% vol/vol) at a flow rate of 1 ml/min. The eluate from the chromatographic separation was passed into a Finnigan SSQ 710C instrument, using an atmospheric pressure chemical ionization (APCI) interface. The instrument monitored ions M/Z 332 and M/Z 366 for marimastat and the internal standard, respectively. Sample size was calculated to ensure ≥90% power to identify a 20% clinical or pharmacological failure rate in either the 5 or 10 mg b.i.d. dose
cohorts. Clinical failure was defined as inability to complete 12 months of therapy due to toxicity. Pharmacological failure was defined as steadystate plasma concentration below the projected therapeutic range based on the IC50 for MMP-2 and MMP-9 (1.5–8 ng/ml). Marimastat is ∼95% protein bound with only 5% circulating in the active free form. Correction for protein binding results in a projected therapeutic target range of 40–200 ng/ml. Consistent with the objectives of this study and in recognition of the limitations of the sample size, relapse-free and overall survival data were not collected or analyzed.
Results From June 1997 to May 1998, 63 patients were enrolled. The median age was 50 years (range 33–75). Patient characteristics are listed in Table 1. Musculoskeletal toxicity affected >90% of patients and was clearly dose related (Table 2). Moderate arthralgia/arthritis (CTC grade 2) was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis (CTC grade 3) was reported by 6% and 23% of patients, respectively. Musculoskeletal toxicity requiring dose modification became apparent after a mean of 133 days (median of 117 days; range 36–346) of marimastat therapy (Figure 1) and generally resolved within 1 month after treatment was interrupted. Other toxicities including headache, nausea and fatigue affected <20% of patients and were never severe. There was no obvious increase in toxicity with concurrent tamoxifen therapy. Steady-state plasma levels within the target range for biological activity (40–200 ng/ml) were rarely achieved (Table 3). Only four patients had even a single value within the target range; plasma levels were undetectable at 35% of the measured time points. Dose interruptions or reductions were required in 44% of patients receiving 5 mg b.i.d. and 35% of patients receiving 10 mg b.i.d. Six patients (19%)
1222 receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. No additional toxicity was identified in the 29 patients who elected to continue marimastat therapy beyond 1 year.
Four patients underwent elective surgery during the initial 12-month study period. Marimastat therapy was held for 3 weeks post-operatively and then resumed at the same dose and schedule. No wound healing or hemorrhagic complica-
Table 2. Toxicitya Marimastat 5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
Mild
4
11
2
6
Moderate
2
9
5
9
Severe
0
1
2
5
Total
6 (75%)
Arthralgia/arthritis
21 (87.5%)
9 (81.8%)
20 (100%)
Myalgia Mild
1
2
0
0
Moderate
1
1
0
1
Severe
0
0
0
1
Total
2 (25%)
3 (12.5%)
0
2 (10%)
Mild
3
1
1
1
Moderate
0
0
0
1
Severe
0
0
0
0
Total
3 (37.5%)
1 (4%)
1 (9%)
2 (10%)
Mild
0
3
1
1
Moderate
0
1
0
1
Severe
0
0
0
0
Total
0
4 (16.6%)
1 (9%)
2 (10%)
Mild
2
4
1
2
Headache
Nausea
Fatigue/asthenia
a
Moderate
0
1
0
0
Severe
0
0
0
0
Total
2 (25%)
5 (20.8%)
1 (9%)
2 (10%)
Worst toxicity experienced per patient according to WHO criteria.
Table 3. Drug delivery Marimastat 5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
7.5
6.9
11.9
12.8
Patients with at least one value in range 40–200 ng/ml
0
1
2
1
Patients with at least one value ≥20 ng/ml
4
2
4
6
Patients requiring dose reduction or delay
5 (62.5%)
9 (37.5%)
3 (27%)
8 (40%)
Patients discontinuing marimastat due to toxicity
0
6 (25%)
3 (27%)
8 (40%)
Patients completing 12 months of marimastat therapy
8 (100%)
17 (71%)
6 (55%)
9 (45%)
Mean trough level (ng/ml)
Target concentration 40–200 ng/ml.
1223
Figure 1. Time to first dose modification for toxicity. (A) All patients enrolled; (B) based on initial dose cohort.
tions were reported. Two patients developed leukemia that appeared unrelated to marimastat therapy. A 71-year-old women was diagnosed with chronic lymphocytic leukemia after 8 months on study. A 55-year-old women who had received prior alkylating agent chemotherapy was diagnosed with acute myelogenous leukemia after 12 months on study.
Discussion This pilot trial was performed as a necessary predecessor to an adjuvant trial of marimastat in patients with early-stage breast cancer. With the exception of musculoskeletal toxicity, marimastat was well tolerated, but plasma levels were well below the target range. Phase I and II studies in patients with advanced malignancies suggested that biologically active levels were achieved with doses of 5–10 mg b.i.d. [11–14]. Trough levels in our patients were below the target range even at the initial measurement; musculoskeletal toxicity prevented any consideration of dose escalation. Trough levels of marimastat in patients with advanced cancer are 2- to 3-fold higher than predicted from the phase I study in healthy volunteers [15]. Though the reasons for this variation remain speculative and are likely multifactorial, the steady-state levels obtained
in our patients more closely mirror the healthy volunteers than patients with advanced disease. Marimastat is the first of several broad-spectrum orally available MMP inhibitors to enter clinical trials. The development of the MMP inhibitors, like that of other antiproliferative rather than cytotoxic compounds, poses a challenge in clinical trial design. The cytostatic mechanism of action of the MMP inhibitors implies time to progression rather than objective tumor response as the proper primary endpoint. Unfortunately, subtle prolongation of time to progression cannot be determined with certainty in uncontrolled trials and may be of minimal clinical benefit in patients with advanced disease. Consequently, the clinical development of marimastat has followed a unique pathway. Initial pharmacokinetic studies in healthy volunteers [16] were followed by novel phase II studies using the rate of rise of serum tumor markers as a surrogate for biological activity. Four hundred and fifteen patients with ovarian, pancreatic, prostatic and colorectal carcinoma were enrolled in six separate trials. All patients had tumor markers increasing by >25% over a 4-week screening period. A combined analysis found a dose-dependent affect on tumor marker rate of rise (P = 0.01) with marimastat treatment. Maximum activity was seen with twice daily dosing achieving a total daily dose of 20 mg/day or higher [17]. Phase III trials in patients with advanced malignancies began early and have thus far yielded mixed results. Three hundred and sixty-nine patients with advanced gastric cancer were randomized to marimastat (10 mg b.i.d.) or placebo. Progression-free survival was significantly longer in marimastattreated patients, with a trend toward improved overall survival [18]. In contrast, overall survival of patients with unresectable pancreatic cancer was not longer in patients randomized to one of three doses of marimastat (5, 10 or 25 mg b.i.d.) compared with treatment with gemcitabine [19]. A phase III trial enrolling 162 patients with glioblastoma who had completed surgery and radiation therapy found no improvement in time to progression or overall survival with marimastat (10 mg b.i.d.) or placebo [20]. Similarly, marimastat (10 mg b.i.d.) did not prolong survival in patients with small-cell lung cancer who had achieved a complete or partial response to initial chemotherapy [21]. Intuitively, the impact of MMP inhibition is expected to be greatest in patients with micrometastatic disease—an intuition that will require commitment of substantial human and financial resources to a randomized trial in the adjuvant setting to test. What prerequisites should we demand before embarking on a large adjuvant trial? At the very least, assurance that chronic therapy can be administered in sufficient doses to support biological activity in the majority of patients treated. Although experience gained in patients with advanced disease is meaningful, even large trials of patients with metastatic disease only provide long-term safety data in a limited number of patients. Although a negative trial in the sense that proceeding to a full-scale adjuvant study with marimastat can not be recom-
1224 mended, we believe this study illustrates the importance of population-specific pilot trials for agents with a primarily static mechanism of action. While no small pilot trial can (or should) eliminate the need for large phase III studies, promising drugs can be screened rapidly eliminating those not suitable for phase III studies, whether due to unforeseen toxicity or unacceptable pharmacokinetics.
Acknowledgements K.D.M. was supported by the American Cancer Society (grant no. CRTG-00-199-01-CCE).
References 1. Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6: 121–125. 2. Azzam HS, Arand G, Lippman ME, Thompson EW. Association of MMP-2 activation potential with metastatic progression in human breast cancer cell lines independent of MMP-2 production. J Natl Cancer Inst 1993; 85: 1758–1764. 3. Monteagudo C, Merino MJ, San-Juan J et al. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol 1990; 136: 585–592. 4. Nakajima M, Welch DR, Wynn DM et al. Serum and plasma Mr 92 000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res 1993; 53: 5802–5807. 5. Zucker S, Lysik RM, Zarrabi MH, Moll U. Mr 92 000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 1993; 53: 140–146. 6. Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K et al. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 1994; 54: 6504–6511. 7. Bergers G, Brekken R, McMahon G et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol 2000; 2: 737–744. 8. Steward WP, Thomas AL. Marimastat: the clinical development of a matrix metalloproteinase inhibitor. Expert Opin Investig Drugs 2000; 9: 2913–2922. 9. Sledge GW Jr, Qulali M, Goulet R et al. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 1995; 87: 1546–1550.
10. Taraboletti G, Garofalo A, Belotti D et al. Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst 1995; 87: 293–298. 11. Primrose JN, Bleiberg H, Daniel F et al. Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen. Br J Cancer 1999; 79: 509–514. 12. Rosemurgy A, Harris J, Langleben A et al. Marimastat in patients with advanced pancreatic cancer: a dose-finding study. Am J Clin Oncol 1999; 22: 247–252. 13. Carmichael J, Ledermann A, Woll PJ. Phase IB study of concurrent administration of marimastat and gemcitabine in non-resectable pancreatic cancer. Proc Am Soc Clin Oncol 1998; 17: 232a (Abstr 888). 14. Eisenberger M, Sinbaldi V, Laufer M et al. Phase I/+ pharmacokinetic evaluation of marimastat in patients with advanced prostate cancer: identification of the biologically active dose. Proc Am Soc Clin Oncol 2000; 19: 336a (Abstr 1320). 15. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–193. 16. Millar AW, Brown PD, Moore J et al. Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Br J Clin Pharmacol 1998; 45: 21–26. 17. Nemunaitis J, Poole C, Primrose J et al. Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res 1998; 4: 1101–1109. 18. Fielding J, Scholefield J, Stuart R et al. A randomized double-blind placebo controlled study of marimastat in patients with inoperable gastric adenocarcinoma. Proc Am Soc Clin Oncol 2000; 19: 240a (Abstr 929). 19. Bramhall S, Rosemurgy A, Brown P et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 2001; 19: 3447–3455. 20. Phuphanich S, Levin V, Yung W et al. A multicenter, randomized, double-blind, placebo controlled trial of marimastat in patients with glioblastoma multiforme or gliosarcoma following completion of conventional, first-line treatment. Proc Am Soc Clin Oncol 2001; 20: 52a (Abstr 205). 21. Shepard F, Giaccone G, Debruyne C et al. Randomized double-blind placebo-controlled trial of marimastat in patients with small cell lung cancer following response to first-line chemotherapy: an NCIC-CTG and EORTC study. Proc Am Soc Clin Oncol 2001; 20: 4a (Abstr 11).
Original article
A randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancer K. D. Miller1*, W. Gradishar2, L. Schuchter3, J. A. Sparano4, M. Cobleigh5, N. Robert6, H. Rasmussen7 & G. W. Sledge1 1
Indiana University, Indianapolis, IN; 2Northwestern University, Chicago, IL; 3University of Pennsylvania, Philadelphia, PA; 4Montefiore Medical Center, New York, NY; 5Rush-Presbyterian Medical Center, Chicago, IL; 6Fairfax Hospital, Fairfax, VA; 7British Biotech, Annapolis, MD, USA
Received 26 September 2001; revised 10 December 2001; accepted 9 January 2002
Background: This pilot trial was performed to evaluate the safety, toxicity and pharmacokinetics of chronic therapy with the matrix metalloproteinase inhibitor marimastat in the adjuvant treatment of breast cancer. Patients and methods: Patients with high-risk node negative or node positive breast cancer received marimastat either 5 or 10 mg p.o. b.i.d. for 12 months. Marimastat was given either as a single agent following completion of adjuvant chemotherapy or concurrently with tamoxifen. Results: Sixty-three patients were enrolled from June 1997 to May 1998. All patients have completed 12 months of treatment or have discontinued therapy due to toxicity, relapse or intercurrent illness. Moderate (WHO criteria) arthralgia/arthritis was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis was reported by 6% and 23% of patients, respectively. Six patients (19%) receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. Trough plasma levels were rarely within the target range for biological activity (40–200 ng/ml) with mean concentration for patients receiving: 5 mg b.i.d. = 7.5; 5 mg b.i.d. plus tamoxifen = 6.9; 10 mg b.i.d. = 11.9; 10 mg b.i.d. plus tamoxifen = 12.8. Conclusions: A randomized adjuvant trial with marimastat is not warranted as chronic administration cannot maintain plasma levels with the target range. Key words: angiogenesis, breast cancer, metalloproteinase, metalloproteinase inhibitor
Introduction
as the dose-limiting toxicity with biologically active levels achieved in patients with advanced malignancy with doses ranging from 5 to 10 mg b.i.d. Matrix metalloproteinase inhibitors significantly curtail primary tumor growth and establishment of metastases in several pre-clinical minimal disease models but fail to shrink large, well established tumors [9, 10]. As such, the most successful clinical application of MMP inhibitors such as marimastat is likely to be in patients with micrometastatic disease. Use in the adjuvant setting requires evidence that drug levels can be maintained above a minimal trough level chronically and safely. This pilot trial was designed to provide such evidence, as a necessary prelude to the appropriate proof of concept adjuvant trials.
The matrix metalloproteinase (MMP) family of enzymes degrade molecules of the basement membrane and extracellular matrix [1]. Under normal physiological conditions the MMPs and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), exist in an exquisite balance. Unbalanced MMP/TIMP expression plays a critical role in cellular movement, invasion, angiogenesis and metastasis [2–7]. Inhibition of the MMPs thus provides a potentially fruitful therapeutic target. Marimastat is a low molecular weight peptide mimetic containing a hydroxamate group that chelates the zinc atom of the active site of the MMPs. Marimastat inhibits a broad spectrum of MMPs and has activity in multiple human tumor xenograft models [8]. Phase I trials identified musculoskeletal syndromes including arthralgia/arthritis, tendonitis and bursitis
Patients and methods
*Correspondence to: Dr K. D. Miller, Division of Hematology/ Oncology, Indiana Cancer Pavilion, 535 Barnhill Drive, RT-473, Indianapolis, IN 46202, USA. Tel: +1-317-274-0920; Fax: +1-317-274-3646; E-mail: [email protected]
Patients with histologically confirmed high-risk node-negative (estrogen receptor-negative primary tumor >1 cm or estrogen receptor-positive tumor >2 cm) or node-positive breast cancer were eligible. All patients had undergone surgical excision of the primary tumor and completed radiation therapy if indicated. All patients were entered within 3 months of completing chemotherapy or initiating tamoxifen treatment. Patients had
© 2002 European Society for Medical Oncology
1221 Table 1. Patient characteristics Marimastat
Median age [years (range)]
5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
44 (33–58)
52 (41–75)
45 (34–65)
55 (43–72)
Stage at diagnosis I
0
4
4
2
II
6
19
6
15
III
0
0
1
1
Unknown
2
1
0
2
Caucasian
5
23
9
19
African–American
1
0
2
0
Asian
0
1
0
0
Hispanic
2
0
0
1
Ethnicity
to have adequate renal, hepatic, hematological and cardiac function. Each local institutional review board reviewed the protocol and individual written informed consent was provided prior to treatment. After eligibility was confirmed, patients were stratified according to planned tamoxifen therapy, age, stage, study site and then randomized to one of two doses of marimastat, either 5 or 10 mg b.i.d. for 12 months. Stratum A enrolled patients receiving adjuvant chemotherapy with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles. Stratum B enrolled patients receiving adjuvant hormonal therapy with tamoxifen 10 mg b.i.d.; patients enrolled in stratum B could have received adjuvant chemotherapy before initiating tamoxifen. Upon completion of the initial 12-month treatment period, patients could elect to continue marimastat therapy for a maximum of 5 years; patients continuing therapy beyond 12 months were evaluated every 3 months. Dose modifications were specified for musculoskeletal toxicity. Interruption of marimastat therapy was mandated for patients with bone, joint or muscle pain restricting activity [common toxicity criteria (CTC) grade ≥2]. Treatment was re-instituted at a once daily dosage (i.e. either 5 or 10 mg daily) once symptoms had subsided. If musculoskeletal symptoms recurred, treatment was discontinued until resolution and then restarted at either 5 or 10 mg every other day. Patients were evaluated monthly for the first 3 months then every 3 months while on study. Plasma samples for steady-state marimastat levels were obtained weekly during the first month, monthly for 2 months and then every 3 months for the first year of therapy; pharmacokinetic samples were not obtained when therapy was interrupted for toxicity. Plasma marimastat concentration was analyzed by a validated liquid chromatography–mass spectrometry procedure. The chromatographic system consisted of Novapak C18 analytical column (Waters Chromatography, Elstree, Hertfordshire, UK) and a mobile phase of methanol/water (55%/45% vol/vol) at a flow rate of 1 ml/min. The eluate from the chromatographic separation was passed into a Finnigan SSQ 710C instrument, using an atmospheric pressure chemical ionization (APCI) interface. The instrument monitored ions M/Z 332 and M/Z 366 for marimastat and the internal standard, respectively. Sample size was calculated to ensure ≥90% power to identify a 20% clinical or pharmacological failure rate in either the 5 or 10 mg b.i.d. dose
cohorts. Clinical failure was defined as inability to complete 12 months of therapy due to toxicity. Pharmacological failure was defined as steadystate plasma concentration below the projected therapeutic range based on the IC50 for MMP-2 and MMP-9 (1.5–8 ng/ml). Marimastat is ∼95% protein bound with only 5% circulating in the active free form. Correction for protein binding results in a projected therapeutic target range of 40–200 ng/ml. Consistent with the objectives of this study and in recognition of the limitations of the sample size, relapse-free and overall survival data were not collected or analyzed.
Results From June 1997 to May 1998, 63 patients were enrolled. The median age was 50 years (range 33–75). Patient characteristics are listed in Table 1. Musculoskeletal toxicity affected >90% of patients and was clearly dose related (Table 2). Moderate arthralgia/arthritis (CTC grade 2) was reported by 34% of patients receiving 5 mg b.i.d. and 45% of patients receiving 10 mg b.i.d.; severe arthralgia/arthritis (CTC grade 3) was reported by 6% and 23% of patients, respectively. Musculoskeletal toxicity requiring dose modification became apparent after a mean of 133 days (median of 117 days; range 36–346) of marimastat therapy (Figure 1) and generally resolved within 1 month after treatment was interrupted. Other toxicities including headache, nausea and fatigue affected <20% of patients and were never severe. There was no obvious increase in toxicity with concurrent tamoxifen therapy. Steady-state plasma levels within the target range for biological activity (40–200 ng/ml) were rarely achieved (Table 3). Only four patients had even a single value within the target range; plasma levels were undetectable at 35% of the measured time points. Dose interruptions or reductions were required in 44% of patients receiving 5 mg b.i.d. and 35% of patients receiving 10 mg b.i.d. Six patients (19%)
1222 receiving 5 mg b.i.d. and 11 (35%) receiving 10 mg b.i.d. discontinued marimastat therapy due to toxicity. No additional toxicity was identified in the 29 patients who elected to continue marimastat therapy beyond 1 year.
Four patients underwent elective surgery during the initial 12-month study period. Marimastat therapy was held for 3 weeks post-operatively and then resumed at the same dose and schedule. No wound healing or hemorrhagic complica-
Table 2. Toxicitya Marimastat 5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
Mild
4
11
2
6
Moderate
2
9
5
9
Severe
0
1
2
5
Total
6 (75%)
Arthralgia/arthritis
21 (87.5%)
9 (81.8%)
20 (100%)
Myalgia Mild
1
2
0
0
Moderate
1
1
0
1
Severe
0
0
0
1
Total
2 (25%)
3 (12.5%)
0
2 (10%)
Mild
3
1
1
1
Moderate
0
0
0
1
Severe
0
0
0
0
Total
3 (37.5%)
1 (4%)
1 (9%)
2 (10%)
Mild
0
3
1
1
Moderate
0
1
0
1
Severe
0
0
0
0
Total
0
4 (16.6%)
1 (9%)
2 (10%)
Mild
2
4
1
2
Headache
Nausea
Fatigue/asthenia
a
Moderate
0
1
0
0
Severe
0
0
0
0
Total
2 (25%)
5 (20.8%)
1 (9%)
2 (10%)
Worst toxicity experienced per patient according to WHO criteria.
Table 3. Drug delivery Marimastat 5 mg b.i.d. (n = 8)
5 mg b.i.d. + tamoxifen (n = 24)
10 mg b.i.d. (n = 11)
10 mg b.i.d. + tamoxifen (n = 20)
7.5
6.9
11.9
12.8
Patients with at least one value in range 40–200 ng/ml
0
1
2
1
Patients with at least one value ≥20 ng/ml
4
2
4
6
Patients requiring dose reduction or delay
5 (62.5%)
9 (37.5%)
3 (27%)
8 (40%)
Patients discontinuing marimastat due to toxicity
0
6 (25%)
3 (27%)
8 (40%)
Patients completing 12 months of marimastat therapy
8 (100%)
17 (71%)
6 (55%)
9 (45%)
Mean trough level (ng/ml)
Target concentration 40–200 ng/ml.
1223
Figure 1. Time to first dose modification for toxicity. (A) All patients enrolled; (B) based on initial dose cohort.
tions were reported. Two patients developed leukemia that appeared unrelated to marimastat therapy. A 71-year-old women was diagnosed with chronic lymphocytic leukemia after 8 months on study. A 55-year-old women who had received prior alkylating agent chemotherapy was diagnosed with acute myelogenous leukemia after 12 months on study.
Discussion This pilot trial was performed as a necessary predecessor to an adjuvant trial of marimastat in patients with early-stage breast cancer. With the exception of musculoskeletal toxicity, marimastat was well tolerated, but plasma levels were well below the target range. Phase I and II studies in patients with advanced malignancies suggested that biologically active levels were achieved with doses of 5–10 mg b.i.d. [11–14]. Trough levels in our patients were below the target range even at the initial measurement; musculoskeletal toxicity prevented any consideration of dose escalation. Trough levels of marimastat in patients with advanced cancer are 2- to 3-fold higher than predicted from the phase I study in healthy volunteers [15]. Though the reasons for this variation remain speculative and are likely multifactorial, the steady-state levels obtained
in our patients more closely mirror the healthy volunteers than patients with advanced disease. Marimastat is the first of several broad-spectrum orally available MMP inhibitors to enter clinical trials. The development of the MMP inhibitors, like that of other antiproliferative rather than cytotoxic compounds, poses a challenge in clinical trial design. The cytostatic mechanism of action of the MMP inhibitors implies time to progression rather than objective tumor response as the proper primary endpoint. Unfortunately, subtle prolongation of time to progression cannot be determined with certainty in uncontrolled trials and may be of minimal clinical benefit in patients with advanced disease. Consequently, the clinical development of marimastat has followed a unique pathway. Initial pharmacokinetic studies in healthy volunteers [16] were followed by novel phase II studies using the rate of rise of serum tumor markers as a surrogate for biological activity. Four hundred and fifteen patients with ovarian, pancreatic, prostatic and colorectal carcinoma were enrolled in six separate trials. All patients had tumor markers increasing by >25% over a 4-week screening period. A combined analysis found a dose-dependent affect on tumor marker rate of rise (P = 0.01) with marimastat treatment. Maximum activity was seen with twice daily dosing achieving a total daily dose of 20 mg/day or higher [17]. Phase III trials in patients with advanced malignancies began early and have thus far yielded mixed results. Three hundred and sixty-nine patients with advanced gastric cancer were randomized to marimastat (10 mg b.i.d.) or placebo. Progression-free survival was significantly longer in marimastattreated patients, with a trend toward improved overall survival [18]. In contrast, overall survival of patients with unresectable pancreatic cancer was not longer in patients randomized to one of three doses of marimastat (5, 10 or 25 mg b.i.d.) compared with treatment with gemcitabine [19]. A phase III trial enrolling 162 patients with glioblastoma who had completed surgery and radiation therapy found no improvement in time to progression or overall survival with marimastat (10 mg b.i.d.) or placebo [20]. Similarly, marimastat (10 mg b.i.d.) did not prolong survival in patients with small-cell lung cancer who had achieved a complete or partial response to initial chemotherapy [21]. Intuitively, the impact of MMP inhibition is expected to be greatest in patients with micrometastatic disease—an intuition that will require commitment of substantial human and financial resources to a randomized trial in the adjuvant setting to test. What prerequisites should we demand before embarking on a large adjuvant trial? At the very least, assurance that chronic therapy can be administered in sufficient doses to support biological activity in the majority of patients treated. Although experience gained in patients with advanced disease is meaningful, even large trials of patients with metastatic disease only provide long-term safety data in a limited number of patients. Although a negative trial in the sense that proceeding to a full-scale adjuvant study with marimastat can not be recom-
1224 mended, we believe this study illustrates the importance of population-specific pilot trials for agents with a primarily static mechanism of action. While no small pilot trial can (or should) eliminate the need for large phase III studies, promising drugs can be screened rapidly eliminating those not suitable for phase III studies, whether due to unforeseen toxicity or unacceptable pharmacokinetics.
Acknowledgements K.D.M. was supported by the American Cancer Society (grant no. CRTG-00-199-01-CCE).
References 1. Matrisian LM. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet 1990; 6: 121–125. 2. Azzam HS, Arand G, Lippman ME, Thompson EW. Association of MMP-2 activation potential with metastatic progression in human breast cancer cell lines independent of MMP-2 production. J Natl Cancer Inst 1993; 85: 1758–1764. 3. Monteagudo C, Merino MJ, San-Juan J et al. Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue. Am J Pathol 1990; 136: 585–592. 4. Nakajima M, Welch DR, Wynn DM et al. Serum and plasma Mr 92 000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res 1993; 53: 5802–5807. 5. Zucker S, Lysik RM, Zarrabi MH, Moll U. Mr 92 000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 1993; 53: 140–146. 6. Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K et al. Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 1994; 54: 6504–6511. 7. Bergers G, Brekken R, McMahon G et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol 2000; 2: 737–744. 8. Steward WP, Thomas AL. Marimastat: the clinical development of a matrix metalloproteinase inhibitor. Expert Opin Investig Drugs 2000; 9: 2913–2922. 9. Sledge GW Jr, Qulali M, Goulet R et al. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst 1995; 87: 1546–1550.
10. Taraboletti G, Garofalo A, Belotti D et al. Inhibition of angiogenesis and murine hemangioma growth by batimastat, a synthetic inhibitor of matrix metalloproteinases. J Natl Cancer Inst 1995; 87: 293–298. 11. Primrose JN, Bleiberg H, Daniel F et al. Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen. Br J Cancer 1999; 79: 509–514. 12. Rosemurgy A, Harris J, Langleben A et al. Marimastat in patients with advanced pancreatic cancer: a dose-finding study. Am J Clin Oncol 1999; 22: 247–252. 13. Carmichael J, Ledermann A, Woll PJ. Phase IB study of concurrent administration of marimastat and gemcitabine in non-resectable pancreatic cancer. Proc Am Soc Clin Oncol 1998; 17: 232a (Abstr 888). 14. Eisenberger M, Sinbaldi V, Laufer M et al. Phase I/+ pharmacokinetic evaluation of marimastat in patients with advanced prostate cancer: identification of the biologically active dose. Proc Am Soc Clin Oncol 2000; 19: 336a (Abstr 1320). 15. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer Inst 2001; 93: 178–193. 16. Millar AW, Brown PD, Moore J et al. Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Br J Clin Pharmacol 1998; 45: 21–26. 17. Nemunaitis J, Poole C, Primrose J et al. Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res 1998; 4: 1101–1109. 18. Fielding J, Scholefield J, Stuart R et al. A randomized double-blind placebo controlled study of marimastat in patients with inoperable gastric adenocarcinoma. Proc Am Soc Clin Oncol 2000; 19: 240a (Abstr 929). 19. Bramhall S, Rosemurgy A, Brown P et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 2001; 19: 3447–3455. 20. Phuphanich S, Levin V, Yung W et al. A multicenter, randomized, double-blind, placebo controlled trial of marimastat in patients with glioblastoma multiforme or gliosarcoma following completion of conventional, first-line treatment. Proc Am Soc Clin Oncol 2001; 20: 52a (Abstr 205). 21. Shepard F, Giaccone G, Debruyne C et al. Randomized double-blind placebo-controlled trial of marimastat in patients with small cell lung cancer following response to first-line chemotherapy: an NCIC-CTG and EORTC study. Proc Am Soc Clin Oncol 2001; 20: 4a (Abstr 11).