Bryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as a weekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease as defined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. There were no disease responses and the main toxicity was myalgia

A Basu

A Clamp

A Gehan

A Latorre

A R Clamp

F H Blackhall

G C Jayson

G Halbert

GC Jayson

GR Pettit

J Kortmansky

J Prendiville

JA Koutcher

L Pagliaro

L Robson

M Markman

M Soukop

MA Rosenthal

ML Varterasian

P Benedetti Panici

P Vasey

PA Philip

R Coleman

Z Schwartz

English

PubMed

Clamp, A.R.

Blackhall, F.

Vasey, P.

Soukop, M.

Coleman, R.

Halbert, G.

Robson, L.

Jayson, G.C.

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A phase II trial of bryostatin-I administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

Bryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as a weekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease as defined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. There were no disease responses and the main toxicity was myalgia. © 2003 Cancer Research UK

Blackhall, Fiona

Clamp, A. R.

Blackball, F. H.

Jayson, G. C.

The University of Manchester - Institutional Repository

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

Canc Res UK Phase I II Comm

White Rose Research Online

This is a repository copy of A phase II trial of bryostatin-I administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma.White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/170596/Version: Published VersionArticle:Clamp, A.R., Blackhall, F., Vasey, P. et al. (6 more authors) (2003) A phase II trial of bryostatin-I administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma. British Journal of Cancer, 89 (7). pp. 1152-1154. ISSN 0007-0920 https://doi.org/10.1038/sj.bjc.6601285eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike (CC BY-NC-SA) licence. This licence allows you to remix, tweak, and build upon this work non-commercially, as long as you credit the authors and license your new creations under the identical terms. 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Short CommunicationA phase II trial of bryostatin-1 administered by weekly 24-hourinfusion in recurrent epithelial ovarian carcinomaAR Clamp*,1, FH Blackhall1, P Vasey2, M Soukop3, R Coleman4, G Halbert5, L Robson6 and GC Jayson1 for theCancer Research UK Phase I/II Committee1Cancer Research UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK; 2ClinicalTrials Unit, Cancer Research UK Department of Medical Oncology, Beatson Oncology Centre, Western Inf irmary, Glasgow G11 6NT, UK; 3Department ofMedical Oncology, Royal Inf irmary, 84 Castle Street, Glasgow, G4 0SF, UK; 4Department of Clinical Oncology, Weston Park Hospital NHS Trust,Whitham Road, Sheff ield S10 0SJ, UK; 5Cancer Research UK Formulation Unit, Department of Pharmaceutical Science, University of Strathclyde, RoyalCollege Building, 204 George Street, Glasgow G1 1XW, UK; 6Drug Development Off ice, Cancer Research UKBryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as aweekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease asdefined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. Therewere no disease responses and the main toxicity was myalgia.British Journal of Cancer (2003) 89, 1152–1154. doi:10.1038/sj.bjc.6601285 www.bjcancer.com& 2003 Cancer Research UKKeywords: bryostatin-1; ovarian cancer; protein kinase C; clinical trialAlthough advanced epithelial ovarian cancer is sensitive toplatinum-containing chemotherapy at first presentation, themajority of patients experience disease relapse and their manage-ment at this stage is often difficult. While rechallenge withplatinum is appropriate for patients with at least a 6-monthdisease-free interval (Markman et al, 1991), those who progresssooner require treatment with newer agents. The response rates tothese, however, are disappointing and therefore a clear need existsfor the development of novel approaches to the management ofrecurrent ovarian carcinoma.Bryostatin-1 is a naturally occurring macrocyclic lactone withantineoplastic activity derived from the marine bryozoan, Bugulaneritina (Pettit et al, 1982). In vitro evidence indicates that its mainmechanism of action is the modulation of protein kinase C activity.How this is antineoplastic is less clear, but may involve apoptosisinduction or immunomodulatory effects (Clamp and Jayson, 2002).During Phase I evaluation of bryostatin-1, myalgia was shown tobe the main dose-limiting toxicity (Philip et al, 1993; Prendivilleet al, 1993; Varterasian et al, 1998), although the mechanism for thisis not fully understood. A maximum tolerated dose of25mgm2week1 was identified when a weekly 24-h infusion wasused (Jayson et al, 1995). Of note, one partial and one minorresponse occurred in two patients with relapsed ovarian cancer inthe trial and so we undertook a Phase II study with this regimen toevaluate further the efficacy of bryostatin-1 in this group of patients.MATERIALS AND METHODSTrial designThis study was a multicentre open label nonrandomised Phase IItrial. The predefined endpoints were response rate and progres-sion-free interval. To ensure a low probability (Po0.05) oferroneously rejecting a treatment that is active in 20% of patients,a minimum of 14 subjects were planned to be treated (Gehan,1961).The study was approved by the Cancer Research CampaignPhase I/II Committee and Central Independent Review Board(CIRB), the National Cancer Institute and Local Regional EthicsCommittees. Written informed consent was obtained from allpatients.PatientsPatients eligible for inclusion were at least 18 years old, withhistologically proven epithelial ovarian cancer that had progressedduring or after at least one platinum-containing chemotherapyregimen. The progression-free interval following last chemother-apy treatment was not a defined selection criterion. All patientshad a life expectancy of X12 weeks and a WHO performancestatus of 0–2. They had radiologically measurable disease X2 cmin two dimensions.Adequate biochemical and haematological functions weredocumented within 1 week of trial entry. Patients were excludedif they had received more than two prior multidrug regimens forovarian cancer and other standard Phase II exclusion criteriaapplied. Systemic steroid administration was contraindicated whilepatients were receiving bryostatin-1.Formulation, dose and administrationBryostatin-1 (US National Cancer Institute, Arizona State Uni-versity, USA) was stored at 41C in flint vials containing 0.1mg oflyophilised bryostatin-1. Prior to administration, it was dissolvedin 1ml of PET (60% polyethylene glycol, 30% ethanol, 10% Tween80) diluent and then diluted with 9ml of 0.9% sodium chloride.The prescribed volume was then drawn up into a polypropyleneReceived 23 May 2003; revised 17 July 2003; accepted 24 July 2003*Correspondence: Dr AR Clamp; E-mail; aclamp@picr.man.ac.ukBritish Journal of Cancer (2003) 89, 1152 – 1154& 2003 Cancer Research UK All rights reserved 0007 – 0920/03 $25.00www.bjcancer.comClinicalsyringe and co-infused intravenously over 24 h with 2 l of 0.9%sodium chloride. Bryostatin-1 was administered weekly at a doseof 25 mgm2 for a planned eight doses.In the presence of Grade 3 or 4 myalgia and/or headache,treatment was delayed for 1 week. If Grade 3 toxicity persisted, thepatient was withdrawn from the trial. If myalgia/headache hadimproved to Grade 2 or better, treatment was recommenced at a25% dose reduction (19mgm2). If XGrade 3 toxicity recurred,treatment was discontinued.If any other Grade 3/4 toxicity (or Grade 1 thrombocytopenia)occurred, treatment was delayed for 1 week and was then restartedat 19mgm2 if recovery had occurred to Grade p1 (except forthrombocytopenia (Grade 0) and neutropenia (Grade 2)). Recur-rent toxicity led to treatment withdrawal. If Grade X2 phlebitisoccurred, treatment was delayed for 1 week and then recom-menced at 25 mgm2. If phlebitis recurred, a 25% dose reductionwas instituted.Monitoring of toxicity and responsePatients were reviewed by a physician weekly, prior to theadministration of bryostatin-1. Included in this review were thepatient’s WHO performance status and the documentation of anynew symptoms and adverse events according to the NCI-CTCcriteria (version 2.0). A full blood count and serum biochemistrywere performed weekly.Evaluable and measurable disease sites were assessed after 8weeks of treatment by the same imaging modality employed priorto study entry. Serum CA-125 levels were determined weekly.Patients with progressive disease were withdrawn from the study.Patients with clear clinical progression were deemed evaluable forresponse, provided that they had received at least four infusions ofbryostatin-1. Those patients who had not received four infusionswere replaced.RESULTSPatient demographicsIn all, 17 patients (median age 60 years, range 43–71) wererecruited. All patients had undergone surgery and platinum-basedchemotherapy after diagnosis. A total of 11 of 16 evaluable patientshad responded to first-line therapy, while two had progressivedisease. 13 patients subsequently received second-line cytotoxicsprior to trial entry. At recruitment all patients had documenteddisease progression, 11 had chemotherapy-resistant and nine hadplatinum-resistant disease as defined by progressive disease ontreatment or disease relapse within 4 months of discontinuingtherapy. Nine patients had WHO performance status 0, 6 PS1 and 2PS2 at entry.Bryostatin-1 administration and responseIn total, 95 doses of bryostatin-1 were given to 17 patients with amedian of six doses each (range 2–9). Four were administered at19 mgm2 due to toxicity. Eight dose delays of 1 week or moreoccurred in eight patients. Two were due to toxicity (one myalgia,one lethargy), three due to concurrent medical problems, one atpatient request due to Grade 2 myalgia and two due toadministrative constraints.Three patients were considered nonevaluable due to markedclinical deterioration prior to completing 4 weeks of bryostatin-1therapy. In all three cases, this was due to rapidly progressivedisease. In all, 14 patients were evaluable. No radiological or CA-125 responses were noted on therapy. Six patients had early diseaseprogression as defined by clear clinical and/or radiologicalevidence of progression prior to the planned assessment aftereight doses of bryostatin-1. Four patients had progressive diseaseand four patients showed disease stabilisation after eight doses. Inall patients with stable disease, treatment was discontinued atthe patients’ request due to the deteriorating quality of lifeassociated with weekly hospital attendances and the side effects ofbryostatin-1. Two of these patients commenced other cytotoxictreatment immediately on withdrawal. In addition, one patientshowed disease stabilisation off antineoplastic treatment for 12months. In the last patient with stable disease, a 94% fall in serumCA-125 was documented 13 weeks after discontinuing bryostatin-1and disease regression was confirmed radiologically.ToxicityToxicities attributed to bryostatin-1 are summarised in Table 1.Eight patients experienced Grade II or III myalgia. This usuallybecame evident after the second bryostatin-1 infusion and itsintensity and duration increased as the treatment continued. Threepatients who experienced Grade 3 myalgia withdrew from the trialat their own request. One patient was withdrawn due to Grade 3lethargy. Notably, the performance status of 13 patients deterio-rated during therapy.DISCUSSIONEfficacyAlthough activity in epithelial ovarian cancer was documented in aPhase I study of bryostatin-1 administered as a weekly 24-hinfusion (Jayson et al, 1995), no disease responses were seen in thisPhase II study. This is in keeping with the disappointing resultsobserved in single-agent Phase II studies performed in otherdisease groups using a variety of administration regimens(summarised in Clamp and Jayson, 2002).It should be noted, however, that although treatment-free interval was not a selection criterion for trial entry, thepatient population treated in this study primarily had chemother-apy-resistant disease. This group is known to have responserates of 0–27% to novel agents tested in the Phase II setting(Latorre et al, 2002). Using the statistical principles appliedTable 1 Toxicity probably/definitely attributable to bryostatin-1(25 mgm2)NCI-CTC v2.0-gradingToxicity 2 3 4Myalgia 4 4 —Fatigue 1 2 —Vomiting — 1 —Lymphocytopenia 6 — —Dermatology-other 2 — —Haemoglobin 2 — —Phlebitis 2 — —Anorexia 2 — —Constipation 2 — —Nausea 1 — —Diarrhoea 1 — —Muscle weakness 1 — —Ocular-other 1 — —Elevated g-GT 1 — —Arthralgia 1 — —Headache 1 — —Injection site reaction 1 — —Stomatitis 1 — —Number of patients with Grade 2 toxicities and above are listed. Only the worstgrade of toxicity noted in each patient is included.Bryostatin in ovarian cancerAR Clamp et al1153British Journal of Cancer (2003) 89(7), 1152 – 1154& 2003 Cancer Research UKClinical(Gehan, 1961), we can only formally exclude activity at the 20%level and so cannot discount equivalent activity with somecytotoxic agents in clinical usage.The demonstration of prolonged stable disease in one patient isconsistent with previous reports with bryostatin-1, particularly inhypernephroma (Pagliaro et al, 2000), although these patientscontinued on therapy until progression. The observation ofdelayed disease regression in one patient is intriguing, but difficultto attribute to bryostatin-1 as initial evidence of response was onlynoted 3 months after therapy was discontinued.ToxicityBryostatin-1 caused significant myalgia, with 48% of patientsexperiencing at least Grade 2 myalgia on treatment. The shortduration of therapy, the rapid onset of myalgia and its increasingduration and intensity with cumulative doses all indicate that thisside effect is likely to be a significant impediment to the furtherclinical development of this agent. This is further reinforced by thefact that three of the four patients in this study experiencing Grade3 myalgia withdrew from treatment at their own request despiteformal documentation of stable disease.Combination regimensGiven its unique side effect profile, it may be that the futureclinical niche for bryostatin-1 in ovarian cancer will be as part ofcombination regimens with conventional cytotoxic agents. Indeed,preclinical data demonstrate synergy with both cisplatin andpaclitaxel (Basu and Lazo, 1992; Koutcher et al, 2000) and thesafety of cisplatin/bryostatin-1 combinations has already beendemonstrated (Rosenthal et al, 1999). It is particularly intriguingthat encouraging Phase II activity with the combination ofcisplatin and tamoxifen has been reported (Benedetti Panici et al,2001), as one of tamoxifen’s possible mechanisms of action is themodulation of PKC activity, suggesting that it could mimicbryostatin-1 (Schwartz et al, 2002). The combination of bryosta-tin-1 and paclitaxel, however, may be hampered by severe myalgiasas reported in one study in oesophageal carcinoma (Kortmanskyet al, 2002).In summary, the results of this trial indicate that bryostatin-1administered alone at a dose of 25 mgm2 as a weekly 24-hinfusion has no role in the management of relapsed chemotherapy-resistant epithelial ovarian cancer. Its future utility will depend onthe successful evaluation of combination regimens with othercytotoxic agents with which it has no overlapping toxicities.REFERENCESBasu A, Lazo JS (1992) Sensitization of human cervical carcinoma cells tocisdiamminedichloroplatinum(II) by bryostatin 1. Cancer Res 52: 3119–3124Benedetti Panici P, Greggi S, Amoroso M, Scambia G, Battaglia FA, GebbiaV, Salerno G, Paratore MP, Mancuso S (2001) A combination of platinumand tamoxifen in advanced ovarian cancer failing platinum-basedchemotherapy: results of a Phase II study. Int J Gynecol Cancer 11:438–444Clamp A, Jayson GC (2002) The clinical development of the bryostatins.Anti-Cancer Drugs 13: 673–683Gehan A (1961) The determination of the number of patients required in apreliminary and a follow up trial of a new chemotherapeutic agent.J Chronic Dis 13: 346–353Jayson GC, Crowther D, Prendiville J, McGown AT, Scheid C, Stern P,Young R, Brenchley P, Chang J, Owen S (1995) A phase I trial ofbryostatin-1 in patients with advanced malignancy using a 24 hintravenous infusion. Br J Cancer 72: 461–468Kortmansky J, Shah M, Ilson D, Kaubisch A, Endres S, Welch M, Gonen M,Kelsen DP, Schwartz GK (2002) Response to the combination ofbryostatin-1 and paclitaxel is dose-dependent. 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J Steroid Biochem Mol Biol 80: 401–410Varterasian ML, Mohammad RM, Eilender DS, Hulburd K, Rodriguez DA,Pemberton PA, Pluda JM, Dan MD, Pettit GR, Chen BD, Al-Katib AM(1998) Phase I study of bryostatin 1 in patients with relapsed non-Hodgkins lymphoma and chronic lymphocytic leukemia. J Clin Oncol 16:56–62Bryostatin in ovarian cancerAR Clamp et al1154British Journal of Cancer (2003) 89(7), 1152 – 1154 & 2003 Cancer Research UKClinical

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A phase I trial of bryostatin-1 in patients with advanced malignancy using a 24h intravenous infusion.

Anti-Cancer Drugs 13: 673–683 Gehan A

Sensitization of human cervical carcinoma cells to cisdiamminedichloroplatinum(II) by bryostatin 1. Cancer Res 52: 3119– Benedetti Panici

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A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

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