PAGE 26 / APRIL 2001
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`Thalidomide-Combo Trials Vary Widely
`
`Joe Vericker/Photobureau
`
`William D. Figg, PharmD,
`said thalidomide probably
`won’t “hit any home runs”
`by itself in prostate cancer
`treatment, but it may be
`useful in combination with
`cytostatic or cytotoxic drugs.
`
`affect PSA, he said. For example, the
`angiogenesis inhibitor TNP470 both
`upregulates and dowregulates, and
`when prostate cancer patients took the
`drug CAI (carboxyamido-triazole), a
`downregulator, PSA levels declined
`even while the patients’ tumor size on
`computed tomography scan was still
`rising.
`Dr. Figg said thalidomide probably
`won’t “hit any home runs” by itself in
`prostate cancer treatment, but it may be
`useful in combination with cytostatic or
`cytotoxic drugs.
`At the NCI, a Phase II trial of doc-
`etaxel with or without weekly thalido-
`mide in androgen-independent disease
`is almost fully accrued, Dr. Figg noted.
`(continued on page 28)
`
`bisphosphonate pamidronate, he noted.
`“We hope to see a lower incidence of
`secondary leukemia in the thalidomide
`arm, which is a problem in myeloma
`therapy.”
`
`Prostate Cancer Responds
`
`A single-agent open-label trial of
`thalidomide at the National Cancer
`Institute of prostate cancer patients
`found declines in prostate-specifc anti-
`gen (PSA) levels in 68 percent of 63
`androgen-independent patients taking
`a high-dose regimen, and in 58 percent
`of men taking low-dose thalidomide,
`reported William D. Figg, PharmD,
`Senior Investigator and Head of NCI’s
`Clinical Pharmacokinetic Section.
`Low dose was 200 mg/day, and
`high dose escalated from 200 to 1,200
`mg/day. Four patients taking low-dose
`thalidomide maintained depressed PSA
`levels for more than 150 days, and two
`of them were considered partial re-
`sponders by bone scan criteria.
`None of the high-dose patients,
`however, had more than a 50% PSA
`response, Dr. Figg noted. “That was
`probably because few patients tolerated
`the high doses, and most had to come
`off trial.” But he added that colleagues
`at the NCI treating Kaposi’s sarcoma
`are using high-dose thalidomide with-
`out the same toxicities—probably
`because the population of patients is
`younger than in advanced prostate can-
`cer trials.
`Dr. Figg pointed out that using
`changes in PSA as a marker probably
`underestimated thalidomide’s actual
`effect on reducing prostate tumors,
`because thalidomide upregulates PSA
`by about 20 percent. Other drugs also
`
`Joe Vericker/Photobureau
`
`Bart Barlogie, MD, PhD,
`said he believes thalidomide
`is an ideal agent to combine
`with myelosuppressive
`cytotoxic drugs, since it is
`minimally bone-marrow
`suppressive.
`
`induction chemotherapy alone or with
`thalidomide.
`The “total therapy” regimen begins
`with vincristine, doxorubicin, and dex-
`amethasone (VAD); followed by dex-
`amethasone, cyclophosphamide, etopo-
`side, and cisplatin (DCEP); then cyclo-
`phosphamide, doxorubicin, and dex-
`amethasone; stem cell transplant; and
`then another cycle of DCEP. A second
`phase consists of two cycles of high-
`dose melphalan.
`Patients are randomized to receive
`or not receive thalidomide throughout
`the year-long program, Dr. Barlogie
`said.
`In a trial planned at his center for
`early indolent (smoldering) myeloma,
`thalidomide will be combined with the
`
`By Robert H. Carlson
`
`N EW YORK CITY—Thalidomide
`
`as an anticancer agent will like-
`ly be best used in combination
`with other drugs, and the selec-
`tion of companion agents being tested
`varies widely. That was the conclusion
`of researchers presenting results here at
`the most recent Chemotherapy Foun-
`dation Symposium and in follow-up
`phone calls at the end of February.
`Combinations with cytotoxic che-
`motherapy agents, steroids, antibiotics,
`and even a bisphosphonate are all
`being tested.
`
`‘Total Therapy’ Includes
`Thalidomide
`
`Thalidomide is an angiogenesis inhi-
`bitor, and its activity as a single agent
`in refractory multiple myeloma was
`confirmed in a report by Bart Barlogie,
`MD, PhD, Director of the Arkansas
`Cancer Research Center in Little Rock.
`He described a trial of 169 patients in
`which 61 responded, including three
`with complete responses, and 20 others
`with regressions of greater than 90 per-
`cent. The overall survival rate with sin-
`gle-agent thalidomide was 55 percent at
`18 months.
`Dr. Barlogie said he believes
`thalidomide is an ideal agent to com-
`bine with myelosuppressive cytotoxic
`drugs, since it is minimally bone-mar-
`row suppressive.
`In an interview after the meeting,
`Dr. Barlogie said a randomized multi-
`ple myeloma trial referred to as “Total
`Therapy II” has already randomized
`more than 300 newly diagnosed multi-
`ple myeloma patients to intensive
`
`Hodgkin’s Disease
`continued from page 25
`
`also to remember that problems can
`arise with relapse. In the case of a male
`who receives initial treatment that is
`nonsterilizing, he may relapse and
`require high-dose treatment. Spermato-
`genesis may have lulled, and there may
`be no further opportunity before steril-
`ization to harvest semen for cryopreser-
`vation. Thus, alternative options have
`to be considered. “Unfortunately,
`because of the evolving nature of proto-
`cols, we are on a moving staircase in
`terms of fertility treatment and progno-
`sis,” Dr. Gosden continued. “It is very
`difficult, in any particular set of circum-
`stances, to predict exactly what the
`effects will be upon a young man or
`woman’s future fertility.”
`
`Act Before Treatment Starts
`
`Therefore, to conserve fertility, it is
`important to act before treatment com-
`
`mences, Dr. Gosden said. In general,
`the options for women are more limited
`than for men. To preserve the possibili-
`ty of a woman’s future genetic parent-
`hood, there is the possibility of embryo,
`oocyte, or ovary banking. One method
`of in vivo protection of the ovaries is to
`perform oophoropexy, in which the
`ovaries are transposed and then
`returned to their original site following
`completion of treatment. There have
`been successes using this approach
`when abdominal radiation treatments
`are required. However, natural fertility
`may not always return after this proce-
`dure.
`Several theoretical approaches are
`now being contemplated. For instance,
`one strategy may be to use oral contra-
`ceptives and gonadotropin-releasing
`hormone agonists in both males and
`females to suppress the gonads and
`thus reduce their radio- or chemo-sensi-
`tivity. However, support for this theory
`is based mostly on animal studies.
`Other theories deal with inventing tar-
`get agents to inhibit apoptotic path-
`
`ways, specifically in oocytes.
`fertile men sometimes cannot produce
`This raises the concern that such
`specimens under the stress of a cancer
`agents would also reduce therapeutic
`diagnosis, or may produce specimens
`benefit. Another concern, said Dr.
`with low sperm counts due to other
`Gosden, is that this technique might
`disease-associated effects.
`conserve germ cells that should have
`Intracytoplasmic sperm injection
`otherwise undergone apoptosis. They
`has revolutionized the treatment of
`may have acquired germ line damage,
`infertility, because only one sperm is
`leading to effects on later reproduction
`needed for fertilization of the partner’s
`such as miscarriage or birth defects.
`egg. And, sperm can be collected either
`One exciting new technology is the
`from ejaculate or from a testicular biop-
`storing of ovarian tissue, either as an
`sy. Another possibility on the horizon
`ovarian biopsy to be cryobanked for
`for men is the preservation of intact
`future transplantation or by recovering
`seminiferous tubules for later trans-
`primordial follicles and maturing them
`plantation. Storage of ovarian or testic-
`in the laboratory for use in in vitro pro-
`ular tissue might also be applied in the
`cedures. Although the latter technology
`future to prepubertal patients, “bring-
`is still a “very long way” from reality,
`ing them into the range of fertility con-
`Dr. Gosden has participated in experi-
`servation for the first time,” he said.
`ments in which autografts of ovarian
`In the meantime, Dr. Gosden urged
`tissue restored estrus cycles in female
`his audience to become aware of the
`sheep.
`problems of infertility and the trauma
`While cryopreservation of semen is
`that is caused in patients as they
`generally accepted as the standard for
`become aware of treatment implica-
`fertility conservation in men, it is not
`tions. A multidisciplinary approach is
`without its fallibilities. The procedure
`important, as is timing, in choosing the
`cannot be used for preadolescents, and
`right procedure for patients.
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`Rangaswamy Govindarajan,
`MD, noted that patients
`treated with irinotecan
`often have Grade 3/4
`diarrhea, which can be
`prolonged and even
`require hospitalization. To
`date there have been no
`such problems in patients
`in a small study who
`have received combined
`irinotecan and thalidomide.
`
`Joe Vericker/Photobureau
`
`his group, called MW16 or CPS16, caus-
`es complete shutdown of vessel growth
`in vitro and is in preclinical trial.
`Another analog, Celgene’s CC5013, is
`in Phase I clinical trials at Dana-Farber
`Cancer Center in Boston. Entremed’s
`thalidomide analog 2-methoxyestradiol
`(2ME) is also in Phase I trial.
`“We are still looking for a thalido-
`mide analog that is more potent, with
`less toxicity,” he said. He speculated
`that angiogenesis inhibitors may find
`their widest use in combination with
`surgery, radiation therapy, or chemo-
`therapy and in patients with minimal
`tumor burden, when there is the most
`recruitment of blood vessels.
`
`The thalidomide-irinotecan combi-
`nation has gotten some notice in treat-
`ment of advanced colon cancer—not for
`response rates greater than with irinote-
`can alone, but because patients had an
`unexpected reduction in severe gas-
`trointestinal side effects usually seen
`with irinotecan.
`Rangaswamy Govindarajan, MD,
`Assistant Professor of Medicine at the
`University of Arkansas for Medical
`Sciences, reported on a trial with 11
`evaluable patients. The irinotecan dose
`was 350 mg/m2 intravenously every
`three weeks, which Dr. Govindarajan
`said is a schedule used in Europe. He
`said the literature shows this is compa-
`
`PAGE 28 / APRIL 2001
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`Thalidomide
`continued from page 26
`
`Activity is being seen in both arms, he
`said, and no unexpected side effects
`have emerged.
`Another NCI Phase II trial is test-
`ing intermittent hormonal ablation with
`or without angiogenesis inhibition.
`Patients receiving six months of leupro-
`lide after irradiation and radical prosta-
`tectomy are randomized to receive
`either thalidomide or placebo.
`Dr. Figg noted that investigators
`are also testing more potent analogs of
`thalidomide. One product patented by
`
`rable in toxicity and response rate to
`the familiar North America schedule of
`125 mg/m2 weekly. The thalidomide
`dose was 400 mg/day.
`Patients had significant reductions
`in Grade 3/4 nausea, vomiting, diar-
`rhea, and abdominal pain as compared
`with irinotecan alone, he noted. “The
`protocol was not written to reduce toxi-
`city, but that was an observation seen
`in all patients.”
`Irinotecan is a very difficult drug to
`give, he added, and about 30 percent of
`patients will have Grade 3/4 diarrhea
`and require hospitalization, which can
`be prolonged for two to three weeks.
`“But we are not seeing any Grade 3/4
`diarrhea in patients who receive irino-
`tecan and thalidomide,” Dr. Govin-
`darajan said.
`
`Thalidomide
`combinations with
`cytotoxic chemotherapy
`agents, steroids,
`antibiotics, and even a
`bisphosphonate
`are all being tested.
`
`The reason for the apparent protec-
`tive effect is unknown. Possible mecha-
`nisms include thalidomide suppression
`of TNF-alpha, some effect on T-helper-
`type-2 cell immune function, or sup-
`pression of cyclooxygenase.
`This trial of 11 patients saw two
`with partial responses and four with
`stable disease. Dr. Govindarajan said
`the response rate was comparable to
`that of irinotecan alone. A prior pilot
`study produced superior results with
`the combination, however, including
`three complete responses in 11 patients,
`“so we don’t know what to make of
`that,” he said.
`
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`PAGE 29 / APRIL 2001
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`unheard of with any other therapy.”
`The addition of glucocorticos-
`teroids allows the use of lower thalido-
`mide doses, for potentially fewer side
`effects, he noted.
`He said his center is now develop-
`ing a program for myeloma using
`thalidomide with the antibiotics clar-
`ithromycin, which appears to greatly
`potentiate responses in patients resis-
`tant to steroids and thalidomide.
`
`No Help in AML
`
`In the one negative thalidomide trial
`reported at the Symposium, the antian-
`giogenic drug did not improve re-
`
`sponse rates of Ara-C and liposomal
`daunorubicin in patients with poor-
`prognosis refractory acute myeloid
`leukemia (AML).
`Jorge Cortes, MD, Associate Pro-
`fessor at the University of Texas MD
`Anderson Cancer Center in Houston,
`described a trial in which 38 patients
`were randomized to liposomal dauno-
`rubicin at 100 mg/m2/day on Days 1-3,
`and Ara-C at 1 gm/m2/day on Days 1-
`4, while 36 others received that regimen
`plus thalidomide, starting at 400
`mg/week and escalating to 600 mg/
`week.
`The early complete response rate
`was approximately the same for both
`
`groups, Dr. Cortes said—about 50 per-
`cent with or without thalidomide.
`Patients who did not respond tended to
`have higher pretreatment vascular
`endothelial growth factor (VEGF) lev-
`els. This suggests that VEGF may be
`mediated through mechanisms other
`than angiogenesis, Dr. Cortes ex-
`plained.
`Patients are being followed to
`determine whether thalidomide affects
`duration of response. “In view of the
`significance of VEGF in the prognosis
`of these patients, further studies are
`warranted using more potent VEGF or
`angiogenesis inhibitors,” he conclud-
`ed.
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`DR. REDDY’S LABS., INC. EX. 1057 PAGE 3
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`Joe Vericker/Photobureau
`
`James Berenson, MD: “We
`treated patients with
`amyloidosis who failed
`other treatments, and most
`responded rather
`dramatically to thalidomide
`or thalidomide and steroids.
`These were patients who
`had extensive disease,
`especially kidney-based but
`also GI-based disease, as
`well as macroglossia.”
`
`Macroglossia Responds to
`Thalidomide & Steroids
`
`At Cedars-Sinai Medical Center in Los
`Angeles, five of six patients with prima-
`ry amyloidosis and renal organ in-
`volvement responded to thalidomide
`and a thalidomide-glucocorticosteroid
`combination, reported James Berenson,
`MD, Director of the Multiple Myeloma
`and Bone Metastases Program.
`“We treated patients with amyloid
`who failed other treatments, and most
`responded rather dramatically to the
`thalidomide or thalidomide and ster-
`oids,” he said. “These were patients
`who had extensive disease, especially
`kidney-based but also GI-based disease,
`as well as macroglossia.” Four patients
`had improved renal involvement, and
`four had what Dr. Berenson termed
`dramatic improvements in quality of
`life. “It was also quite impressive to
`see improvement in albumin levels,
`which almost returned to normal with
`the addition of low-dose thalido-
`mide,” he said. “That is pretty much
`
`Jorge Cortes, MD: “In view
`of the significance of VEGF
`in the prognosis of these
`patients, further studies are
`warranted using more
`potent VEGF or angiogenesis
`inhibitors.”
`
`Joe Vericker/Photobureau
`
`