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`A Phase II Trial of Bryostatin-1 for Patients with
`Metastatic Renal Cell Carcinoma
`
`Lance Pagliaro, M.D.1
`Danai Daliani, M.D.1
`Robert Amato, D.O.1
`Shi-Ming Tu, M.D.1
`Donnah Jones, R.N.2
`Terry Smith, M.S.3
`Christopher Logothetis, M.D.1
`Randall Millikan, M.D.1
`
`1 Department of Genitourinary Medical Oncology,
`M. D. Anderson Cancer Center, Houston, Texas.
`
`2 Community Clinical Oncology Program, M. D.
`Anderson Cancer Center, Houston, Texas.
`
`3 Department of Biostatistics, M. D. Anderson Can-
`cer Center, Houston, Texas.
`
`Supported in part by National Institutes of Health
`grant U01 CA70172, Phase II/III Clinical Trials of
`Anticancer Agents. L.P. and R.M. are pleased to
`acknowledge support from the American Cancer
`Society in the form of a Career Development
`Award.
`
`The authors thank Ms. Sherryl Smith for secretarial
`assistance.
`
`Address for reprints: Randall Millikan, M.D., M. D.
`Anderson Cancer Center, Department of Genitouri-
`nary Medical Oncology, 1515 Holcombe Boule-
`vard, Box 13, Houston, Texas 77030.
`
`Received August 4, 1999; revisions received De-
`cember 13, 1999 and March 29, 2000; accepted
`March 29, 2000.
`
`© 2000 American Cancer Society
`
`BACKGROUND. Patients with metastatic renal cell carcinoma have a poor prognosis
`and no standard therapy is available. The authors performed a Phase II trial of the
`novel agent bryostatin-1 in this patient population.
`METHODS. In all, 30 patients with measurable, previously untreated metastatic
`renal cell carcinoma were studied. Patients had excellent physiologic reserve and
`preserved performance status. Bryostatin-1 (25 mg/m2) was given in the PET
`(polyethyleneglycol, ethanol, and Tween 80) formulation as a 30-minute intrave-
`nous infusion on Days 1, 8, and 15 of each 28-day cycle. In general, treatment was
`continued until disease progression.
`RESULTS. Two patients had significant objective responses, although methodologic
`problems made interpretation difficult. The median time to progression for all
`patients was 2.1 months; the median overall survival was 13.1 months. The treat-
`ment was generally well tolerated. Myalgia was the most common adverse event.
`One patient died while on study. This was a sudden death for a patient receiving
`a 15th cycle of therapy. Aside from this patient (for whom the correlation of study
`drug to death was not clear), no Grade 4 nonhematologic toxicity was encountered
`in more than 150 treatment courses delivered.
`CONCLUSIONS. There is minimal, if any, clinically relevant single-agent activity of
`bryostatin-1 at this dose and schedule for patients with metastatic renal cell
`carcinoma. Cancer 2000;89:615– 8. © 2000 American Cancer Society.
`
`KEYWORDS: bryostatin, renal cell carcinoma, Phase II, clinical trial.
`
`Despite the introduction of interferon-a, interleukin-2 (IL-2), and
`
`combinations of these with cytotoxics, such as fluoropyrimidines,
`objective response rates in patients with metastatic renal cell carci-
`noma (RCC) remain low.1 Improved survival of a treated cohort by
`virtue of any systemic therapy has not yet been rigorously established,
`although patients with favorable prognostic features (intact perfor-
`mance status and disease confined to lymph nodes or lung) are
`reported consistently to have response rates in the range of 30 – 40%.
`These responses can be durable: Responding patients have had a
`median survival of 2–3 years in many reports. Nonetheless, the overall
`median survival of patients with metastatic RCC remains approxi-
`mately 1 year. In this context, the testing of new agents, especially
`those representing novel paradigms, remains a high priority for clin-
`ical investigation.
`Bryostatin-1 is a novel marine natural product that was reported
`first in 1982.2 It has pleotropic effects on myelopoietic cells3 and was
`shown in preclinical evaluation to have both antiproliferative activity4
`and differentiating activity.5 Modulation of cytokines, especially IL-2
`signaling, suggested a possible therapeutic role in tumors that were
`responsive to IL-2 therapy.6 As a potent compound with a novel
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`CANCER August 1, 2000 / Volume 89 / Number 3
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`mechanism of action, bryostatin-1 was designated a
`high priority agent by the National Cancer Institute
`(NCI).7 Herein, we report the results of a single-insti-
`tution Phase II trial of bryostatin-1 in patients with
`metastatic RCC who had received no prior cytotoxic or
`immunotherapy for their disease.
`
`MATERIALS AND METHODS
`Patient Characteristics
`Between June 1996 and July 1998, 30 patients were
`registered from the Department of Genitourinary
`Medical Oncology at the University of Texas M. D.
`Anderson Cancer Center. All patients provided writ-
`ten, informed consent. All registered patients are re-
`ported for both toxicity and response.
`All patients had histologically confirmed RCC, al-
`though biopsy of metastatic sites was not required if
`histologic confirmation was available for the primary
`tumor and the presentation was considered typical. All
`patients had bidimensionally measurable disease (pa-
`tients with disease confined to bone were not consid-
`ered measurable). All patients had excellent physio-
`logic reserve. Eligibility criteria included a Zubrod
`performance status of 0 –1, hemoglobin (without
`transfusion support) $ 9.5 g/dL, baseline white blood
`cell count and platelet count in normal range, esti-
`mated creatinine clearance of 60 mL per minute, and
`transaminases # 2 times the upper limit of normal.
`Patients were excluded for any of the following rea-
`sons: a known history of human immunodeficiency
`virus infection, uncontrolled central nervous system
`metastases, any cerebral vascular event (including
`TIA) within the previous 6 months, evidence of bifas-
`cicular block or i chemia on electrocardiogram or
`symptoms of arteriosclerosis, or pregnancy, lactation,
`or inability to practice contraception.
`Prior to initiation of systemic therapy, the primary
`tumor was controlled either by angioinfarction or ne-
`phrectomy. This was done to conform to standards of
`immunotherapy for RCC at the time the trial was
`initiated. In those patients with the primary tumor still
`intact at registration, systemic treatment was initiated
`as soon as patients were fully recovered from the
`procedure performed to provide local control.
`
`TABLE 1
`Characteristics of Patients at the Time of Protocol Registration
`
`Median age in yrs (range)
`Gender
`Male
`Female
`Zubrod performance status
`0
`1
`2
`Metastatic sites (no. of patients)
`Lymph node
`Lung
`Liver
`Bone
`Miscellaneous
`No. of sites
`1
`2
`. 2
`No. of discrete metastatic lesions
`Solitary
`2–5
`. 5
`Control of primary tumor
`Nephrectomy
`Angioinfarction
`Laboratory studies: median (range)
`Hemoglobin (g/dL)
`LDH (i.u./L)
`Alkaline phosphatase (i.u./L)
`Creatinine (mg/dL)
`
`58 (38–78)
`
`24
`6
`
`11
`17
`2
`
`20
`17
`8
`6
`19
`
`6
`9
`15
`
`3
`6
`21
`
`20
`10
`
`13 (10.3–15.8)
`510 (162–2374; ULN, 618)
`115 (53–574; ULN, 126)
`1.3 (0.8–2.2)
`
`LDH: lactose dehydrogenase; ULN: upper limit of normal.
`
`Treatment
`All patients were treated according to the dose and
`schedule set by the NCI on the basis of earlier work,
`namely, bryostatin-1 at 25 mg/m2 intravenously (i.v.)
`over 1 hour on Days 1, 8, and 15 of each 28-day cycle.
`This was given in the polyethyleneglycol, ethanol, and
`Tween 80 (PET) formulation, a vehicle consisting of
`60% polyethylene glycol 400, 30% ethanol, and 10%
`Tween 80. All i.v. bags and tubing were non-PVC.
`In general, unless unacceptable toxicity was en-
`countered, therapy was continued until progression or
`“maximum benefit” was achieved, as judged by the
`treating physician. No objective response was re-
`quired to continue therapy.
`
`Statistical Considerations
`This study was conducted using an optimal two-stage
`design,8 looking for a 20% response rate as the thresh-
`old of interest. One of 14 patients in the first stage
`responded, and, thus, accrual was expanded to 30
`patients to define the response rate with reasonable
`confidence intervals.
`
`RESULTS
`The baseline characteristics of registered patients are
`summarized in Table 1. Note that, although an eligi-
`bility criterion was a Zubrod performance status of
`0 –1, an audit of the protocol revealed 2 patients who
`were enrolled with a Zubrod performance status of 2.
`Most patients had numerous involved sites (Table 1).
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`Overall, 18 patients (60%) had metastatic sites beyond
`lymph node or lung. The median number of cycles
`delivered was 4 (range, 1–14 cycles).
`As of February 2000, all patients have either pro-
`gressed on therapy (21 patients) or have gone off study
`for other reasons (9 patients); 22 patients have died.
`The median time to progression for all patients was 2.1
`months. The Kaplan–Meier estimate of median sur-
`vival for all patients was 13.1 months.
`Objective tumor regression occurred in two pa-
`tients. The first patient, a male age 49 years, had a
`large superior mediastinal mass that was progressive
`on serial imaging and presumed on clinical grounds to
`be due to metastatic RCC. This patient went on to
`have a radiographic complete response. After 12
`courses, the patient underwent a superior mediastinal
`lymph node dissection. No residual malignancy was
`found. This patient remains free of detectable disease
`in any site more than 2 years from the initiation of
`therapy.
`A second patient, a female age 69 years with typ-
`ical, diffuse pulmonary metastases (hundreds of nod-
`ules up to 1.5 cm in greatest dimension, diffusely
`involving both lungs), also had a dramatic regression.
`However, in this case, bryostatin-1 was started imme-
`diately after angioinfarction of the primary tumor;
`thus, we cannot be sure that this was not a “sponta-
`neous” regression induced by control of the primary
`tumor. Such cases of remarkable regression after con-
`trol of the primary tumor are uncommon but well
`known.9 This patient completed 6 cycles of therapy
`and has only two very small (, 1 cm) and radiograph-
`ically stable nodules remaining by computed tomog-
`raphy evaluation of the chest. Other than these mini-
`mal
`residual abnormalities,
`this patient has no
`detectable disease more than 18 months from the
`initiation of therapy.
`In general, toxicity was acceptable, with no Grade
`4 nonhematologic adverse events encountered (Table
`2). Two patients had Grade 4 lymphopenia that re-
`solved without apparent clinical consequence. As ex-
`pected from Phase I experience,10 myalgia was the
`most commonly encountered adverse event, although
`this was mild in most cases. Three patients reported
`significant fatigue that was severe enough in one case
`to contribute to a decision to discontinue therapy,
`although the patient did complete 10 months of treat-
`ment. Two patients had a novel reaction consisting of
`generalized “bronzing” of the skin with prolonged ex-
`posure to bryostatin-1. This was of no concern to
`either patient. One additional patient had mild hyper-
`pigmentation that was confined to sun-exposed areas.
`In all, 3 of 7 patients who were treated for more than
`6 months had clinically evident skin changes.
`
`Bryostatin-1 in Renal Cell Carcinoma/Pagliaro et al.
`
`617
`
`TABLE 2
`Summary of Observed Toxicities
`
`Adverse reaction
`
`Grade 1–2
`
`Grade 3
`
`Grade 4
`
`Hematologic
`Anemia
`Lymphopenia
`Granulocytopenia
`Nonhematologic
`Renal toxicity
`Myalgia
`Fatigue
`Dyspnea
`Dermatitis
`Hyperpigmentation
`
`n/a: Not assessed.
`
`11
`1
`1
`
`9
`4
`n/a
`—
`—
`3
`
`2
`2
`2
`
`—
`3
`3
`2
`1
`—
`
`—
`2
`—
`
`—
`—
`—
`—
`—
`—
`
`One patient died while still on active therapy. This
`male age 79 years received 14 cycles of bryostatin-1
`without incident, maintaining a fully active perfor-
`mance status with clinically stable disease. During the
`15th course of therapy, the patient experienced sud-
`den death. This patient had a 30 pack-year smoking
`history and a remote history of laryngeal carcinoma
`from which he was apparently cured. In addition, he
`had mild hypertension for which he took diltiazem,
`but there was no known history of coronary artery
`disease. Although some correlation to bryostatin-1 is
`possible, it seems likely that this was a cardiovascular
`death that was unrelated to therapy.
`
`DISCUSSION
`The optimal systemic treatment for patients with RCC
`is not known; indeed, to date, no therapy can be
`considered standard. In the context of this therapeutic
`deficiency and on the basis of plausibly relevant im-
`munomodulatory effects (and possibly direct cyto-
`toxic effects), we have conducted a Phase II trial of
`bryostatin-1 at the dose level and schedule set by the
`NCI. The two major clinical responses observed re-
`quire some comment. The first patient did not have
`histologic confirmation of his solitary metastatic site.
`Because there was no residual tumor in the resected
`material after systemic treatment, we have no tissue
`confirmation that this patient had metastatic RCC.
`However, spread to mediastinal nodes is common (9
`of 30 patients in this study had mediastinal lymph
`node metastases), and it remains our impression that
`this patient had metastatic RCC. In the second patient,
`bryostatin-1 was started immediately after angioin-
`farction of the primary tumor, and the observed re-
`sponse could have been a “spontaneous” regression.
`Thus, although both of these responses were quite
`dramatic, neither can be claimed unequivocally to be
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`CANCER August 1, 2000 / Volume 89 / Number 3
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`due to bryostatin-1. However, even if both of these
`responses are granted as bona fide treatment-related
`responses, an objective response rate of 2 of 30 (7%;
`95% confidence interval, 1–22%) does not suggest that
`bryostatin-1 has any role in the treatment of patients
`with metastatic RCC as a single agent in the dose and
`schedule that we studied. Moreover, the observed me-
`dian survival of only 13.1 months was disappointing.
`For example, a trial of 5-fluorouracil, interferon-a, and
`IL-2 conducted in the same department with similar
`eligibility criteria showed a median survival of 22.9
`months.11
`Recently, preliminary data have suggested some
`promising bryostatin combinations. Thus, despite
`these disappointing results with bryostatin-1 as a sin-
`gle agent, we do see good reasons to explore combi-
`nations of bryostatin-1 with other agents in the treat-
`ment of patients with RCC. Clinical studies along these
`lines already are underway.
`
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