Irwin H. Krakoff

Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.

Platinum Coordination Complexes in Cancer Chemotherapy

Effective anti-cancer agents are sometimes found by large-scale testing against animal tumours and sometimes by the rational design of chemicals. More often than not, however, they originate from a chance observation made in another area of research. Such was the discovery of the platinum compounds with anti-cancer activity which arose from the now famous observation of Professor Rosenberg and his colleagues that electrolysis products from platinum electrodes could inhibit the growth of bacteria. Observations of this sort remain a scientific curiosity unless followed up by skilful research. Rosenberg’s publication on “Platinum Compounds; A New Class of Antitumour Agent”, which identified the inhibitory compound, was soon followed by a series of papers showing that cis-dichlorodiammine platinum (11) (commonly referred to nowadays as cis Pt 11) was an inhibitor of many different types of animal tumour. The cancer clinician has relatively few drugs available for treatment of inoperable cancer. None is highly selective for cancer cells and their use is almost always associated with serious toxicity to the patient. Furthermore, there are still many types of cancer, particularly the solid carcinomas of the lung and digestive tract, which do not respond well to any form of treatment. Naturally, a new class of agent with high activity in animal tests will arouse great interest, since a novel structure may indicate a novel mechanism of action against those human cancers which do not respond at present to chemotherapy. The growing interest in the platinum compounds was evident from work presented at the first International Symposium on the bacterial , viral and anti-tumour activities of platinum compounds held at Michigan State University in 1970 and later at a special session of the VII International Congress on Chemotherapy in Prague in 1971. Both meetings were, however, preliminary inasmuch as clinical studies of the platinum compounds were only just beginning. The Second International Symposium on Platinum Coordination Complexes in Cancer Chemotherapy, held at Wadham College, Oxford in April, devoted one day to the results of the first clinical trials of cis Pt 11, and so for the first time enabled a preliminary assessment of the likely usefulness of platinum complexes in the clinic. Besides the session on clinical trials there were four half-day sessions on the chemistry of the platinum compounds, their reactions with biomacromolecules and their biological effects in in vitro systems and in whole animals. From this material an attempt can now be made to answer the three questions that must be asked of any new class of anti-cancer agent. What is the mechanism of action of the agent and does it act quite differently from known anti-cancer agents ? How effective is the agent in the clinic when used either alone or in combination, and is it useful in the treatment of cancers which do not respond to known agents ? Is it possible to design analogues of the compound with less side effects and more potent anti-cancer action ? A review of the chemistry of the coordination complexes delivered by Dr R. J. P. Williams, of the University of Oxford, made it quite clear that other types of complex could be synthesised with properties similar to

Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid)

SummaryWe have recently begun a phase II trial in patients with osteosarcoma who developed pulmonary metastases during adjuvant chemotherapy or who presented with pulmonary metastases that persisted despite chemotherapy. Eligible patients were rendered free of visible disease by surgery. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (MTP-PE, CGP 19835A lipid) (2 mg/m2) was infused twice weekly for 3 months. In five patients, a single tumor nodule recurred within 6 weeks after completion of therapy. These lesions were resected and submitted for pathological examination. Tissue specimens obtained after therapy were compared to those obtained before therapy. All the patients showed a histological change in the characteristics of the pulmonary tumors. In three patients, peripheral fibrosis surrounded the tumor and inflammatory cell infiltration and neovascularization were present. This is in contrast to central necrosis, with viable peripheral tumor cells and no inflammatory response observed in lesions resected following chemotherapy. In a fourth case, evidence of early fibrotic changes was found. This and the fifth case showed a change in malignant characteristics, from high grade before liposomal therapy to low grade after therapy. The present study provides evidence for a biological effect of liposomal MTP-PE.

Retinoic acid and interferon combination studies in human cancer

Retinoic acid and interferon-alpha have limited single-agent activity in advanced cancer. Cell culture data indicate that in combination these agents have enhanced activity (modulating growth and differentiation) in a number of malignant cell types. Recent clinical work in advanced squamous cell carcinoma reports major activity with this regimen. This paper reviews the preclinical and clinical data testing retinoic acid in combination with interferons and presents recent work integrating these agents with radiotherapy in locally advanced cervical cancer.

Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes.

SummaryA new series of highly lipid-soluble cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane)platinum(II) complexes were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), 195pt nuclear magnetic resonance (NMR)]. cis-bis-Neopentanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II) (NPDP), cis-bis-neodecanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II) (NDDP), and cis-bis-n-decanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II) (DEDP) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for toxicity and antitumor activity. The entrapment efficiency of the liposomal platinum (L-Pt) complexes (L-NPDP, L-NDDP, L-DEDP) was >95%, and the stability in 0.9% NaCl solution at 4°C was >95% at day 14 in each case. The LD50 values of L-NPDP, L-NDDP, and L-DEDP when injected i.v. were 30, 54, and 150 mg/kg, respectively. L-NPDP, L-NDDP, and L-DEDP had no significant nephrotoxicity [as evidenced by a lack of elevated blood urea nitrogen (BUN) levels]. The percentages of T/C obtained after a single i.p. injection of the optimal dose of L-NPDP, L-NDDP, and L-DEDP tested against L1210 leukemia were 175%, 187%, and 212%, respectively [160% for cisplatin (CDDP)]. When a multiple i.p. injection schedule was used (on days 1, 5, and 9), L-NPDP, L-NDDP, and L-DEDP were more active than CDDP (percentage of T/C: 312%, 312%, 277%, and 220%, respectively). When injected i.v., only L-NDDP showed significant activity against L1210 leukemia i.v. (percentage of T/C: 186%). L-NDDP and L-DEDP were markedly active against L1210 leukemia resistant to CDDP (percentage of T/C: 200% and 145% vs 112% for CDDP). L-NPDP, L-NDDP, and L-DEDP also had good activity against i.p. B16 melanoma when they were injected i.p. on days 1, 5, and 9 (percentage of T/C: 206%, 225%, and 306%, respectively). L-NDDP and L-DEDP were more effective than CDDP in inhibiting the growth of liver metastases of murine M5076 reticulosarcoma, whereas L-NPDP was not active. The results obtained to date suggest that L-NDDP is the best L-Pt-complex candidate for further developmental studies.

Phase I trail of droloxifene in patients with metastatic breast cancer

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10-to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.

Phase I trial of 1-(2′-deoxy-2′-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity

SummaryFMAU (1-[2′-deoxy-2′-fluoro-l-β-D-arabinofuranosyl]-5-methyluracil) a newly synthesized fluorinated nucleoside, has potent in vitro antiviral and antileukemic activity and is active in murine leukemia lines resistant to cytosine arabinoside. In the initial phase I trial neurotoxicity, characterized by extrapyramidal dysfunction, was found to be the dose-limiting toxic effect, and a dosage of 32 mg/m2/day for 5 days was suggested for phase II studies. We report a second phase I study of FMAU using this schedule. Mild, transient neurologic dysfunction was encountered in patients treated at the starting dose of 4 mg/m2/day × 5 days and became severe and irreversible in two patients who received the highest cumulative doses administered at the 8 mg/m2/day × 5 days level. Both severely affected patients died. Severe neurotoxicity developed and progressed in these patients despite serial neurologic examinations, including detailed neuropsychologic tests implemented in an effort to detect early neurotoxicity. Because of these findings, further study of this drug as an antileukemic agent cannot be recommended. If it is to be used as an antiviral agent, further phase I study at lower doses is advised.

Phase I evaluation of all-trans retinoic acid with and without ketoconazole in adults with solid tumors.

PURPOSE All-trans retinoic acid (RA) induces accelerated plasma all-trans RA clearance, presumably via cytochrome P450 enzymes. This accelerated metabolism has been shown to be inhibited in the short term by the cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time. PATIENTS AND METHODS Using a randomized crossover study design, we randomly assigned six patients to receive all-trans RA (45 mg/m2 orally twice per day for 14 days of a 21-day cycle) for cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 days) for cycle 2, and seven patients to receive the same treatment in the reverse order. Plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2. RESULTS There was a marked decrease in plasma all-trans RA levels after 14 days of treatment, as measured by the area under the concentration-time curve (AUC), regardless of whether ketoconazole was given (from a baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/mL/h; P = .123). This lack of effect on plasma all-trans RA levels was not due to inadequate plasma ketoconazole levels. Ketoconazole administration was associated with more toxicity. No objective tumor responses were observed. CONCLUSION Ketoconazole does not appear to maintain adequate plasma all-trans RA levels over time.

Metastatic adenocarcinoma of the endometrium treated with 13-cis-retinoic acid plus interferon-alpha.

Phase II trials of the novel biologic combination of 13-cis-retinoic acid plus interferon (IFN)-α have achieved major activity in advanced squamous cell carcinomas of the skin and cervix, but not of the lung or head and neck. Very limited study of this combination has occurred in cancers other than those of squamous type. Although uncommon, cases of unresectable or metastatic endometrial adenocarcinoma are virtually incurable, and chemotherapy has had no impact on survival in these cases. This report describes our use of 13-cis-retinoic acid plus IFN-α to treat a case of cisplatin- and hormone-resistant, locally advanced and distantly metastatic adenocarcinoma of the endometrium. In this worst-prognosis case, the biologic therapy achieved a major response, which persisted for 4 months. Based on the dramatic activity in this case, we believe that depthful mechanistic and clinical study of this promising new biologic combination should be expanded to include non-squamous tumors of many different sites and histopathologic types.

Phase I clinical trial and pharmacokinetic evaluation of 4′-0-tetrahydropyranyladriamycin (THP-adriamycin)

SummaryTetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with α, β, and γ half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, <10% of the compound was eliminated in the urine within 24 h.