`
`®
`
`Ribomustinbendamustine
`
`
`
`Breckenridge Exhibit 1147
`Breckenridge v. Novartis lPR2017-01592
`Ribomustin Label
`
`Page 1
`
`
`
`Table of contents ____ _
`
`1.
`
`Historical review ..........•...........•....•.........•..••...•.. 7
`
`Product description .......................... , .. , ... , ..... , , ..... 8
`2.
`2.1 Description of the finished medicinal product ........................ 8
`2.2 Chemical name and structural formula of the active ingredient .......... 8
`2.3 Presentation ..... , ...................................... , ....... 8
`2.4
`Indications ...................... , .............................. 9
`2.5 Contraindications ........................................ :' ...... 9
`2.6 Type of use .................................•..............•.... 9
`2.7 Dosage by individual and daily doses ............................... 10
`
`Toxicology .................................................. , . 11
`3.
`Acute toxicity ...................•..... , ........................ 11
`3.1
`3.2 Subchronic toxicity .......................... , ................... 11
`3.3 Mutagenic and carcinogenic effects .. , ........ , .... , .... , ..... , .... 12
`3.4 Reproductive toxicity and teratogenic activity ......... , . , ........... 12
`
`Pharmacology ..............•..............................•..• 13
`4'
`Efficacy in animal models and cell culture ........................... 13
`4.1
`4.2 Mechanism of action ..................•......•.................• 16
`
`Pharmacokinetics .......................... , .....•...•.......... 17
`5.
`Site of absorption and absorption kinetics. , . ' ...................... 17
`5.1
`5.2 Protein binding ...........................................••... 17
`5.3 Concentration in tissue. , ..........................•............. 17
`5.4
`CSF penetration ............................................•... 17
`5.5 Placental transfer ......•............ ' .. , , ... , . , .......... , ...... 17
`5.6 Excretion in breast milk ................................ ' ......... 17
`5.7 Biological half-life ........•..•.......••..•...................... 18
`5.8 Elimination .............................................•...... 18
`
`3
`
`
`
`Breckenridge Exhibit 1147
`Breckenridge v. Novartis lPR2017-01592
`Ribomustin Label
`
`Page 3
`
`
`
`5.9 Elimination in impaired renal function •.•.....•.......•..........•. 18
`5.10 Elimination in impaired hepatic function .................•......... 18
`5.11 Dialysability ...................................•.. ·· .. ·.· ..... · 18
`5.12 Metabolism .............................•..................... 19
`
`Clinical efficacy ..........•..................................... 20
`6.
`Hodgkin's disease (stage lI·iV) .................................... 20
`6.1
`6.2 Non-Hodgkin lymphoma (NHl) ..............•.......•............ 22
`6.3 Chronic lymphocytic leukemia (Cll) ................................ 29
`6.4 Plasmocytoma (multiple myeloma I MM) .......•................... 32
`6.5 Breast cancer ..•..................•........•................... 35
`6.6
`in clinical evaluation -lung cancer ................................ 39
`6.7
`in clinical evaluation - gastrointestinal tumours ...................... 39
`6.8
`in clinical evaluation - head and neck cancer ........................ 40
`6.9 Effects on lymphocyte subsets .................................... 40
`
`Tolerability ................................•................... 43
`7.
`7.1 General. ...................................................... 43
`7.2 Hematopoietic system .......•........•......................•... 43
`7.3 Gastrointestinal tract ........................•.............•..... 44
`7.4 Nervous system ................................................ 44
`7.5 Allergic reactions I hypersensitivity ............•......•............ 44
`7.6 Cardiovascular system ........................................... 44
`7.7 Skin, mucosa .................................................. 45
`7.8
`local irritations ................................................ 45
`7.9 Other side effects ............ '" ... " ...... , .... ' .............. 45
`7.10 Note for drivers ................................•............... 45
`
`Overdosage ................................................... 46
`8.
`8.1 Main symptoms and general signs of overdosage " .................. 46
`8.2 Treatment of overdosage and intoxication .......................... 47
`
`9.
`
`Summary ..................................................... 48
`
`10. References .................................................... 49
`
`11.
`
`Abbreviations ..................•.............................. 55
`
`Directions for Use for Physicians ................................... 56
`
`5
`
`
`
`6
`
`Breckenridge Exhibit 1147
`Breckenridge v. Novartis lPR2017-01592
`Ribomustin Label
`
`Page 5
`
`
`
`Historical review
`
`Benchmustine (IMET 3393) was developed in the early 1960s by
`Ozegowski and co-workers (44) at the Institute of Microbiological
`and Experimental Therapy in Jena (Germany). The aim of the synthesis
`was to conlbine a purine and amino acid antagonist with an alkylating
`nitrogen mustard group (bifunctional alkylating agent). A major
`advantage of the newly developed compound compared to chlorambu(cid:173)
`cil. for example. was its water solubility (45). Anger et aJ. (2) published
`initial results of the successful clinical use ofbendamustine in plasmo(cid:173)
`cytoma patients. Bendamustine was marketed from 1971 to 1992
`under the trade name Cytostasanll by the Jenapharm company. Since
`1993 the cytostatic is being marketed by ribosepharm GmbH under
`the name Ribomustin":
`
`7
`
`
`
`Product description ___ _
`
`2.1 Description of the finished medicinal product
`
`Ribomustin'¥
`Active ingredient: bendamustinehydrochloride
`
`2.2 Chemical name and structural formula of
`the active ingredient
`(5-[bis(2-chloroethyl)-amino]-1-methyl-2-benzimidazole) butyric acid hydro(cid:173)
`chloride (Figure 1).
`
`Structural formula
`
`~:::~:) N ' (YN )-(CH,h-COOHoHCI
`~N
`I
`CH,
`Figure 1: Structural formula of bendamustinehydrochloride
`
`Empirical formula
`C,.H"CI,N.,O,·HCI
`
`Molecular weight
`394.7 (calculated with reference to the anhydrous substance)
`
`2.3
`I
`
`Presentation
`One vial with pierceable stopper with 55 mg of the dried substance contains
`25 mg ofbendamustinehydrochloride.
`
`One vial with pierceable stopper with 220 mg of the dried substance contains
`100 mg ofbendamustinehydrochloride.
`
`8
`
`
`
`2.4 Indications
`Ribomustin" is indicated as single-agent therapy or in combination with other
`antineoplastic drugs for the treatment of the following malignancies:
`
`• Hodgkin's disease (stages II-IV)
`• non-Hodgkin'S lymphoma
`• plasmocytoma
`• chronic lymphocytic leukemia
`• breast cancer.
`
`2.5 Contra indications
`Ribomustin··· should not be used in the following cases:
`
`• known hypersensitivity to bendamustine and! or mannitol
`• pregnancy. presumed pregnancy and during breast feeding
`• impairment of renal function (glomerular filtration rate < 30 mJlminute)
`• severe liver parenchymal damage
`• jaundice
`• existing severe bone marrow depression and severe blood count abnormalities
`• major surgery less than 30 days before starting therapy
`• infections, especially associated with leukopenia (risk of generalization of infection).
`
`2.6 Type of use
`Ribomustin" is administered as a short intravenous infusion over 30 to 60 minutes
`after reconstitution in accordance with the instructions.
`
`The ready-to-use solution is prepared as follows:
`
`Dissolve the contents of one Ribomustin~ vial with pierceable stopper containing
`25 mg bendamustine in 10 1111 by shaking.
`Dissolve the contents of one Ribomustin~' vial with pierceable stopper containing
`100 mg bendamustine in 40 ml by shaking.
`
`As soon as a clear solution is obtained (this usually takes 5 to 10 minutes), dilute the total
`dose of Rib om us tin x immediately with 0.9 % NaCI solution to produce a final volume of
`about 500 ml.
`
`9
`
`
`
`2.7 Dosage by individual and daily doses
`Bendamustine is administered as monotherapy or in combination with other chemothera(cid:173)
`peutic agents in a variety of dosages and regimens. There is no "standard dosage" and no
`"standard regimen". Some widely used dosages and regimens which have been evaluated
`in clinical studies are given below. For further dosages and regimens please refer to the
`medical literature; information is also available on request.
`Treatment should be terminated if the leukocyte and/or platelet count has decreased to
`levels s 3,000/)l1 and s 7s,000/)l1 respectively.
`Ribomustin"" treatment can be continued after the leukocyte count has increased to <:
`4,000/)l1 and the platelet count to ~ 100,000/)l1.
`The portion offree bendamustine hydrochloride may be increased by up to 30% if the level
`of albumin in plasma is very low (s 30 gil). A dose reduction may therefore be considered
`in such cases. Examples of different dosages and regimens (depending on the indication):
`
`Hodgkin's disease (stages /I-IV)
`"pEYBe regimen'"
`25 mg/m'
`daunorubicin
`bleomycin
`10 mg/m2
`vincristine
`1.4 mg/m'
`Ribomustin'!
`50 mg/m'
`
`Non-Hodgkin's lymphoma
`"DOP regimen'"
`
`Ribomustin~
`vincristine
`prednisone
`
`60 mg/m2
`2 mg/m'
`100 mg/m2
`
`on days 1+15
`on days 1 +15
`on days 1+15
`on days 1- 5
`
`on days 1-5
`on day 1
`on days 1-5
`
`repetition of the cycle after 4 weeks.
`
`repetition of the cycle after 3 weeks.
`
`Plasmocytoma
`"Dr regimen":
`Ribomustin'
`prednisone
`
`120-150 mg/m2 on days 1+2
`60 mg/m'
`on days 1-4
`
`repetition of the cycle after 4 weeks.
`
`Chronic lymphocytic leukemia
`Ribomustin'
`80-100 mg/m'
`
`on days 1 +2
`
`repetition of the cycle after 4 weeks.
`
`Breast cancer
`"EMF regimen";
`120 mg/m2
`Ribomustin l
`40 mg/m2
`methotrexate
`600 mg/m2
`s-fluorouacil
`"Second line therapy":
`100-150 mg/m2 on days 1 +2
`Ribomustinx.
`
`on days 1 +8
`on days 1+8
`on days 1 +8
`
`repetition of the cycle after 4 weeks.
`
`repetition of the cycle after 4 wee ks .
`
`. Note:
`No dose recommendations can currently be given for children, since there is no experience
`with this age group.
`
`10
`
`
`
`Toxicology _______ _
`
`3.1 Acute toxicity
`The LD~) in mice after intravenous and intraperitoneal administration is
`80 mg/kg body weight. The LD~) in rats after intravenous administration
`is 40 mg/kg body weight (62).
`
`3.2 Subchronk toxicity
`Bendamustine hydrochloride was administered orally to rats in dosages of 10,
`20,40,80 and 160 mg/kg daily over a period of28 days. The substance was
`not lethal up to a dose of 40 mg/kg. Hematologic and non-hematologic side
`effects were slight to moderate and reversible after treatment termination. The
`LD~) was reached at dosages of~ 80 mg/kg daily.
`In dosages of 80 and 160 mg/kg bendamustine induced bone marrow aplasia,
`atrophy oflymphatic tissue and histopathologic abnormalities of the kidneys
`and intestine. There was no evidence of damage to other organs (33).
`
`Subchronic toxicity studies in dogs were performed with a 30-minute daily
`intravenous infusion administered in three 4-day cycles. Each of the cycles was
`followed by a 31-day recovery phase. The following side effects were observed
`at doses of 6.6 mg/kg/ day: vomiting, salivation, weight loss and loss of appe(cid:173)
`tite. During the recovery phase evacuation ofliquid stool and behavioural
`changes were observed. Gross examination revealed mucosal hyperemia and
`intestinal hemorrhagic zones in these animals. Microscopic analysis also revea(cid:173)
`led pronounced changes to lymphatic tissue as an indicator of immuno(cid:173)
`suppression, and changes to kidneys, testes and prostate. Doses of 3.3 and
`1.65 mg/kg/day. however, were tolerated with only minor toxicity (slightly
`reduced food consumption, slight weight loss. dose-dependent leukocyte
`suppression) (11).
`
`11
`
`
`
`3.3 Mutagenic and carcinogenic effects
`
`Bendamustine induces chromosome aberrations and exhibits mutagenic activity in cell
`culture and animal models (22; 54; 55).
`
`Lung tumours and mammary carcinomas were detected in mice after administration of
`bendamustine (15).
`
`Reproductive toxicity and teratogenic activity
`Bendamustine was embryotoxic and teratogenic in pregnant mice (24).
`
`12
`
`
`
`Pharmacology _____ _
`
`1 4.1
`
`i
`
`Efficacy in animal models and cell culture
`Schnabel et al. (62) demonstrated with three experimental murine tumours
`(leukemia LAJ 1, sarcoma 180, Ehrlich ascites carcinoma) that bendamustine is
`comparable to cyclophosphamide in its suppressive effect on tumour growth.
`
`Further studies (14) have evaluated the antineoplastic activity of bendamustine
`in 8 experimental murine tumour models using different transplantation tech(cid:173)
`niques and forms of administration. Bendamustine exhibited a suppressive
`effect on tumour growth for 6 tumours (Ehrlich ascites carcinoma,leukemia
`L1210,leukemia P388, melanoma B16, Lewis lung carcinoma and lymphoma
`ABDt6) (4).
`
`Strumberg et al. (66) studied the cytotoxic effect of bendamustine on human
`ovarian and mammary carcinoma cell lines (including cisplatin and doxorubi(cid:173)
`cin resistant cell lines). Besides the cytotoxic activity the investigators also
`demonstrated incomplete cross-resistance with other alkylating agents (cyclo(cid:173)
`phosphamide, melphalan and carmustine).
`
`Schwaenen et al. (65) studied the in vitro induction of apoptosis in B-CLL
`cell lines by bendamustine and fludarabine alone and in combination. Benda(cid:173)
`mustine showed dose-related apoptosis induction of 8% to 94% after 48 hours.
`
`13
`
`
`
`In 10 of 12 13-CLL cell lines the combination ofbendamustine and fludarabine resulted
`in a synergistic effect after 48 hours, i.e. a lA-fold higher apoptosis rate than expected
`(see Figure 2).
`
`[i f1udarabine 0.7 ~glml
`• bendamustine 2 "glml
`If expected
`• combination
`
`95,99
`
`100
`
`BO
`
`!60
`
`.~
`t>.
`~ 40
`
`20
`
`o .....L_-=='_""'=
`24 h
`
`48h
`time
`
`72h
`
`Figure 2: Enhanced apoptosis of B·CLL lymphocytes on incubation with bendamustine I fludarabine (accor·
`ding to Schwaenen et al.l
`
`Chow et al. (12) studied the ;/1 vitro induction of apoptosis and inhibition of proliferation of
`neoplastic cells in low-grade NHL using combinations of established cytotoxic drugs with
`bendamustine. The combination ofbendamustine with cladribine resulted in additive or
`even synergistic effects on apoptosis and inhibition of cell proliferation on all tested cell
`populations (DOHH-2;WSU-NHl; ex vivo cells of patients with ClL, leukemic low(cid:173)
`grade 13-NHl, T-NHL). In contrast, the combination ofbendamustine with either doxoru(cid:173)
`bicin or mitoxantrone showed antagonistic effects both on apoptosis and inhibition of cell
`proliferation (Figure 3).
`
`Combination index of tested drug combinations
`
`7.5
`
`5.0
`
`2.5
`
`CI
`
`Antagonism
`CI>1
`
`Synergism
`CI<I
`
`--~--
`
`~O~---------------------------------------------~------
`p
`A
`A
`A
`
`14
`
`B+M
`
`B+(
`
`Figure 3: Combination index ((I) for apoptosis (A) and Inhibition of proliferation (P):
`Orug combinations: B ... 0: bendamustine t doxorubicin,
`S ... M; bendamustine ... mitoxantrone,
`B+ C: bendamustine ... cladribine
`
`
`
`Dendamustine induced apoptosis was p53 independent, thus the apoptosis cascade seems
`not to be influenced by bendamustine. Therefore, the expression patterns of the drug com(cid:173)
`binations containing bendamustine depended on the expression caused by the combination
`partner (doxorubicin, mitoxantrone or c1adribine).
`
`This cell model demonstrated that bendamustine has a different mechanism of interaction
`than that of purine analogs and a different manner of induction of apoptosis than alcylating
`agents.
`
`These results suggest that schedules using combinations of bendamustine and anthracy(cid:173)
`clines should not be recommended for the treatment oflow-grade NHL, whereas benda(cid:173)
`mustine combined with c1adribine could be considered for the development of future
`treatment strategies.
`
`Schleucher et al. (61) studied the interaction ofbendamustine with vinorelbine, 5-FU and
`paclitaxel in cytotoxicity assays. In addition. he studied whether the efficiency is influenced
`by the sequence of the drugs.
`Dendamustine showed significant cytotoxicity in human tumour cell lines, even in those
`with MDR-1 activity. The sequence ofbendamustine and 5-FU showed additive to syner(cid:173)
`gistic interactions. Bendamustine and vinorelbine showed a sequence dependent synergism
`in 2 different cell lines. The cytotoxic activity of paclitaxel may be increased in combinati(cid:173)
`on with bendamustine.
`
`MDA-MB231
`
`MCF-7
`
`synergistic
`additive
`synergistic
`antagonistic
`synergistic
`antagonistic
`antagonistic
`synergistic
`synergtstlc
`synergistic
`synergistic
`synergistic
`
`Interactions of the cytotoxic agents bendamustine, 5-FU, paclitaxel, and vinorelbine
`on breast cancer cell lines MCF-7 (wild type) and MDA-MB231 a
`MCF-7
`bendamustine before 5-FU
`5-FU before bendamustine
`bendamustine before 5-FU
`5-FU before bendamustine
`bendamustine before paclitaxel
`paclitaxel before bendamustine
`bendamustine before paclitaxel
`paclitaxel before bendamustine
`bendamustine before vinorelbine
`vinorelbine before bendamustine
`bendamustine before vinorelbine
`vinorelbine before bendamustine
`
`MD231
`
`MCF-7
`
`MDA-MB231
`
`• incubations with bendamustine. paclitaxel. and vinorelbine for 2 h. with 5-FU for 24 h
`
`15
`
`
`
`4.2
`
`Mechanism of action
`Bendamustine is a bifunctional alkylating agent with antineoplastic and cytocidal properties
`(Figure 4).
`
`benzimidazole ring:
`purine. analogue
`
`N-mustard-group:
`alkylating agent
`(reduced toxicity due
`to electron affinity)
`
`alkanccarhoxylic acid:
`provides water-solubility
`
`Figure 4: Chemical-functional structure of bendamustine
`
`The efficacy is attributable mainly to crosslinking of the DNA single and double strands by
`alkylation. This produces a disturbance of the matrix function of DNA and DNA synthesis.
`There is also crosslinking bet\\'een DNA and proteins and between proteins themselves.
`It is not yet known whether the benzimidazole ring possesses additional antimetabolite pro(cid:173)
`perties (18; 30; 66; 68).
`
`15
`
`
`
`Pharmacokinetics ____ _
`
`5.1 Site of absorption and absorption kinetics
`Not applicable since intravenous administration.
`
`5.2 Protein binding
`The substance is bound to plasma proteins (preferentially albumin) to the
`extent of 95% (16; 41; 42). The protein binding behaviour of bendamustine
`has been shown to be unaffected by low plasma albumin levels, age over
`70 years and advanced tumour stages (15).
`
`5.3 Concentration in tissue
`No cumulation is to be expected (42; 47).
`
`5.4 CSF penetration
`No information is available regarding CSF penetration.
`
`5.5 Placental transfer
`No information is available regarding placental transfer.
`
`5.6 Excretion in breast milk
`No information is available regarding excretion in breast milk.
`
`17
`
`
`
`5.7 Biological half-life
`
`Following i. v. bolus injection of bendamustine in the usual therapeutic dosages, the plasma
`level in man follows a biphasic exponential pattern. The elimination half-life tl/~(l is bet(cid:173)
`ween 6 ·and 10 minutes, and the terminal elimination half-life t,nB between 28 and 36
`minutes. After i. v. administration in several studies the central volum~ of distribution was
`between 8.6 and 11.21. Under steady state conditions the volume of distribution was
`15.8 - 20.5 I (41; 42).
`
`I ts
`
`I
`
`Elimination
`Elimination is rapid, biphasic and predominantly renal. Mean total clearance was calculated
`as 528.9 - 826.2 m1/minute. The following fractions, referred to the total amount of admi(cid:173)
`nistered parent compound, were detected in urine: bendamustine 45.3%, hydroxy-benda(cid:173)
`mustine 23.8%, an unidentifi!Cd polar metabolite 13.4%, B-hydroxy-bendamustine 8%, an
`unidentified apolar metabolite 5.1 % and N-demethyl-bendamustine 1.5%. Mainly polar
`metabolites are eliminated by the biliary route (41; 42).
`
`~ 15.9
`
`!
`
`Elimination in impaired renal function
`Dendamustine is predominantly eliminated by the ~enal route. The drug should
`not be given to patients with impaired renal function (glomerular filtration rate
`< 30 mllminute).
`
`, 5.10 Elimination in impaired hepatic function
`
`Bendamustine is metabolized in the liver ·and eliminated to a small extent (mainly polar
`metabolites) via the biliary system. The drug should not be given to patients with severe
`hepatic parenchymal damage and jaundice.
`
`5.11 Dialysability
`It is not yet known whether bendamustine or its metabolites are dialyzable.
`
`18
`
`
`
`5.12 Metabolism
`Bendamustine is metabolized mainly in the liver. The main biotransformation product is a
`cytotoxic hydroxy derivative (B-hydroxybendamustine), which is formed by hydroxylation
`of the butanoic acid side chain. This substance shows elimination kinetics similar to those
`of the parent compound (till about 19 minutes). In the dose range 0.5- 5.0 mg/kg, clearan(cid:173)
`ce and the AUe (13-0H-bendamustine)/ Aue (bendamustine) ratio are non-dose depen(cid:173)
`dent. Further identified metabolites are monohydroxybendamustine, dihydroxybendamusti(cid:173)
`ne, hydroxy-13-hydroxl'bendamustine and N-demethylbendamustine (41; 42; 48) (Figure 5).
`
`acH,CH, .......
`
`C1(H,eH,/NyyN ~ )--CH,cH,CH,cOOH
`~' i ..............
`~"
`aeH.CH./ yy >-~N CH.CH.CH,eoDi
`
`/
`
`/
`
`CH,.
`rnmdolnustrne
`
`"-..
`
`HOCH,cHr
`....... N
`
`N
`
`I
`CH,
`OH·bend.:tmustine
`
`/
`.
`
`N
`oeH.(H, ....... N
`O(H,eH,/ yy ~
`~ N /-CH,(H,cH.eoDH
`
`N •• cm.thY,b.L,",",,;o.
`
`CH.
`di·OH·bendamll~tlJ1l·
`
`poior fTlet"bolite {I}
`Ilt'lilr rnetaoolitt UI!
`apolar met.,bolite- (III)
`
`Figure 5: Metabolism of bendamustine (ace. to Preiss et al.)
`
`CH.CNOHCN.COOH
`
`C1CH.CH ........
`aCH,CH,/NyyN>-
`V---N
`I
`CH,
`11·0H-bcndamL!'Slin~
`
`j
`
`HoeH,CH, .......
`
`(!CH,CH,/ NyyN
`
`lAN>---CH.CHOHCH'COOH
`I
`CH.
`OtH~·OH·b\>nd.nlliJstint:'.
`
`19
`
`
`
`Clinical efficacy _____ _
`
`6.1 Hodgkin's disease (stage II-IV)
`
`Initial research findings have shown that bendamustine is at least as effective as cyclo(cid:173)
`phosphamide (3).
`
`In a further prospective randomized study, Hache et co-workers (31) compared various
`chemotherapy protocols in 73 evaluable patients with Hodgkin's disease stage 11m or
`IV (Ann Arbor classification). Only patients with primary or secondary resistance to the
`Cvpp regimen (cyclophosphamide / vinblastine / procarbazine / prednisone) were
`enrolled in the study. One treatment cycle lasted 28 days, and day 16 to day 28 were
`treatment-free.
`
`Treatment regimens
`OBVB Cn = 38)
`Daunorubicin
`Bleomycin
`Vincristine
`Bendamustine
`
`25 mg/m2 i.v. on days 1 + 15
`10 mg/m2 i.v. on days 1 + 15
`1.4 mg/m2 i.v. on days 1 + 15
`50 mg i.v. on days 1 - 5
`
`ABVO Cn = 35)
`Doxorubicin
`Bleomycin
`Vincristine
`Dacarbazine
`
`25 mg/m2 i.v. on days 1 + 15
`10 mg/m2 i.v. on days 1 + 15
`1.4 mg/m2 i.v. on days 1 + 15
`150 mg/m2 i.v. on days 1 - 5
`
`Study results
`
`Number of
`patients
`
`CR
`n(%)
`
`CR+PR
`n(%)
`
`OBVB
`ABVO
`
`38
`35
`
`9 (24)
`4 (11)
`
`26 (69)
`29 (83)
`
`Median
`remission
`duration
`(months)
`4.5
`3.4
`
`Median
`survival
`
`(months)
`19.5
`11.3
`
`20
`
`
`
`Conclusions:The combination therapy containing bendamustine is equivalent in effective(cid:173)
`ness to the reference therapy but is better tolerated.
`
`Herold et al. (25) evaluated the efficacy of cyclic alternating chemotherapy in the therapy
`of patients with non-pretreated advanced Hodgkin's disease (stage II1A, IIIB, IVA, IVB)
`in a multi centre randomized study.
`
`Treatment regimens
`cvpp (n = 40)*
`' 600 mg/m2 i.v. on days 1 + 8
`Cyclophosphamide
`~--~~---------I·----
`6 mg/m2 i.v. on days 1 + 8
`Vinblastine
`100 mg oral on days 1 - 14
`Procarbazine
`40 mg/m2 oral on days 1 - 14
`Prednisolone
`
`DBVB - alternating with the above CVPP regimen (n = 40)**
`25 mg/m2 i.v. on days 1 + 15
`Daunorubicin
`10 mg/m2 i.m. on days 1 + __ 1_5 ___________ _
`Bleomycin
`2 mg i.v. on days 1 + 15
`Vincristine
`30 mg/m2 i.v. on days 1 -__ ?, _____ ,_, __ , _______ _
`Bendamustine
`* treatment-free interval day 15 to day 28; prednisolone only in cycles 1 and 4
`** treatment-free interval day 16 to day 28
`
`The results of this treatment demonstrate that the two therapeutic regimens are equally
`effective. No statistically significant differences were detectable.
`
`Study resu Its
`
`CVPP
`
`Number of
`patients
`40
`
`CR
`n(%)
`24 (60)
`
`PR
`n(%)
`6 (15)
`
`CR+PR
`n(%)
`30 (75)
`
`No
`remission
`10 (25)
`
`DBVB - alternating with the above CVPP regimen
`40
`
`I 23 (57.5) I 12 (30)
`
`I
`
`35 (87.5)
`
`5 (12.5)
`
`With the aim of reducing the risk oflate complications of combined radio chemotherapy
`in patients with non-pretreated Hodgkin's disease and of minimizing risk factors, Herold
`et al. (26; 27) studied the efficacy of reduced radio- and chemotherapy as sandwich therapy.
`The following parameters were regarded as particular risks: large mediastinal tumour,
`B-symptoms, extensive abdominal involvement, extranodal involvement - especially of
`the lungs -, unfavourable histologic subtypes - especially lymphocyte-depleted histologic
`subtypes -, increase in sedimentation rate of more than 50 mm in the first hour.
`The therapeutic regimen developed in the pilot study is shown below.
`
`21
`
`
`
`Therapeutic regimen
`CVPP/ABVCy hybrid regimen
`600 mg/m2 i.v. on day 1
`Cyclophosphamide
`6 mg/m2 i. v. on day 1
`Vinblastine
`100 mg/m2 oral on days 1 - 7
`Procarbazine
`40 mg/m2 oral on days 1 - 14
`Prednisolone
`25 mg/m2 i.v. on day 8
`Doxorubicin
`15 mg/m2 i.m. on day 8
`Bleomycin
`2 mg i.v. on day 8
`Vincristine
`30 mg/m2 i.v. on days 8 - 12
`Bendamustine
`Treatment-free interval day 15 to day 28; repetition day 29
`
`Radiotherapy was administered with a reduced focal dose of25 Gy as inv~lved field
`irradiation, and chemotherapy comprised six cycles.
`
`In addition to the favourable results in terms of remission rate (81% patients with CR,12%
`with PR and only 7% non-responders) the 9-year survival data of the pilot study are signi(cid:173)
`ficant.
`
`After a median observation period of 108 months, 27 of 35 patients are in their first com(cid:173)
`plete remission. Eight patients relapsed (after 14.20.30.31.36.38.48 and 77 months).
`Renewed complete remission could be achieved in 3 of these 8 patients by salvage therapy.
`The proportion of patients classifiable as responders (:0: rate of freedom from therapeutic
`failure) was 78% (after 5 years) and 70% (after 9 years). Total survival after 5 and 9 years was
`83% and 73% respectively.
`
`In a subsequent phase III study (28). 100 non-pretreated patients were treated with either
`cyclophosphamide or bendamustine. each combined with vinblastine. procarbazine, predni(cid:173)
`solone. doxorubicin. vincristine and bleomycin and also received radiotherapy.The results
`of the above pilot study were confirmed. Comparable remission and survival rates were
`determined for both therapeutic regimens. The CR rate was 88% in the bendamustine
`group and 81% in the cyclophosphamide group. The 5-year total survival rate at interim
`analysis (68 months follow-up) was 83% and 80% respectively (bendamustine and cyclo(cid:173)
`phosphamide group).
`
`6.2 Non-Hodgkin lymphoma (NHL)
`
`6.2.1 Indolent lymphoma
`Ruffert et al. (56) studied the efficacy ofbendamustine in combination with vincristine
`and prednisolone (BOP) in 31 patients with refractory. progressive. malignant NHL (see
`table).
`
`22
`
`
`
`Patient characteristics
`Stages
`11
`IIIA/IIIB
`IV A / IV B
`20
`Histology according to Kiel classification
`Low grade
`10
`12
`Intermediate grade
`9
`High grade
`PrevIous treatment
`Knospe
`COP
`CHOP-Bleo
`Relapse rate
`1" relapse
`2nd relapse
`3,d relapse
`
`9
`23
`15
`
`14
`8
`9
`
`Treatment reg.imen
`Chemotherapy was given according to the following regimen (repetition day 22):
`
`Bendamustine .
`
`Vincristine
`Prednisolone
`
`60 mg/m' i. v. as a short infusion over 1 hour on days 1 - 5
`or 100 mg/m' i.v. 011 days 1 - 3
`1.4 mg/m' i.v. on day 1 (up to max. 2 mg)
`100 mg/m' i.v. on days 1 - 5
`
`The study results conclusively show the effectiveness of the treatment regimen as a second(cid:173)
`line or third-line therapy in patients with Knospe, COP and CHOP-Bleo refractory malig(cid:173)
`nant NHL.
`
`Study resu Its
`
`Number of
`patients
`31
`
`CR
`n(%)
`12 (38.7)
`
`PR
`n(%)
`16 (51.6)
`
`CR + PR
`n(%)
`28 (90.3)
`
`NC
`n(%)
`0(0)
`
`PO
`n(%)
`3 (9.6)
`
`The patients with complete remission showed a remission duration of 5 to 24+ months
`(median 12.4 months) and patients with PR showed a remission duration of 1 to 19 months
`(median 9.8 months). The total survival rate was' 68% for the observation period. Malignant
`NHL was only in 13% of the patients the cause of death.
`
`23
`
`
`
`Evaluation of the study results taking into account the malignancy-grade showed that
`although no complete remissions were achieved for low-grade NHL, all patients achieved
`partial remission. The remission duration was between 3 and 19 months.
`
`Six and five patients with intermediate or high-grade NHL, respectively, achieved complete
`remission, and 5 and 2 patients, respectively, achieved partial remission. The results obtained
`in these patient samples are particularly to be emphasized since these patients had previous(cid:173)
`ly been given both the COP and the CHOP-B1eo regimen. It can therefore be assumed
`that no cross-resistance to cyclophosphamide, doxorubicin and chloran1bucil was present
`(see also 59). Subjective tolerability was very good (see table below).
`
`Toxicities
`Organ (incidence)
`
`Hemoglobin (6.4%)
`Granulocytes (35.4%)
`Platelets (16.1 %)
`Bleeding (0%)
`Liver enzymes (0%)
`Stomatitis (9.6%)
`Nausea/vomiting (19.3%)
`Diarrhea (16.1%)
`Alopecia (0%)
`Infections (16.1%)
`Fever (16.1%)
`-----_.
`Exanthem (12.9%)
`Hypotension (12.9%)
`Phlebitis (35.4%)
`
`0
`29
`20
`26
`31
`31
`28
`25
`26
`31
`26
`26
`27
`27
`20
`
`WHO grade
`2
`1
`2
`3
`0
`0
`2
`4
`2
`0
`3'
`4
`1
`2
`3"
`
`-
`
`1
`1
`4
`2
`0
`0
`1
`2
`3
`0
`0
`0
`3
`2
`6
`
`3
`0
`4
`0
`0
`0
`0
`0
`0
`0
`2'
`1
`0
`0
`T
`
`4
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`• Pneumonia, herpes zoster, cystopyelitis
`*. Thrombophlebitis after intravenous bolus injection
`
`In an ongoing study (21; 9), 39 pretreated patients with relapsed and advanced low-grade
`NHL have so far been treated with 120 mg/m2 bendamustine given as a short infusion over
`1 hour on days 1 and 2. Previous treatment comprised cyclophosphamide; ifosfamide,
`anthracyclines, chlorambucil, etoposide and vinca alkaloids. Complete remission has been
`observed in 4 of 32 patients so far evaluable. 53% of the patients showed partial remission
`(17 patients) and 19% (6 patients) were found to have a stable NC status. The current
`median remission duration is 10+ months. Side effects have generaIly been mild and were
`limited to myelosuppression, gastrointestinal toxicity and allergic reactions (see following
`table).
`
`24
`
`
`
`Side effects (Heider et al.)
`Toxicity
`
`Leukocytes
`Platelets
`Hemoglobin
`Nausea/vomiting
`Allergies
`Cardiotoxicity
`Neurotoxicity
`Alopecia
`
`0
`5
`25
`8
`20
`39
`43
`43
`43
`
`WHO grade
`2
`10
`3
`8
`5
`3
`0
`0
`0
`
`1
`25
`15
`27
`18
`1
`0
`0
`0
`
`3
`3
`0
`0
`0
`0
`0
`0
`0
`
`4
`0
`0
`0
`0
`0
`0
`0
`0
`
`In an open label single centre pilot study, Weide et al. (67) evaluated a new effective treat(cid:173)
`ment for refractory or relapsed indolent lymphomas with the combination ofbendamusti(cid:173)
`ne/mitoxantrone/rituximab (BMR). 31 patients received the BMR-regimen.
`
`Patient characteristics
`The median age of the patients was 67 (range 32-82). Median number of previous treat(cid:173)
`ment regimens was 2 (1-6).4 patients were refractory to fludarabine treatment.
`
`Secondary high grade !.:.-yn_l-,-p_h_om_a_.f-n __ =_5 ___ -l
`Indolent lymphoma
`n=17
`
`n=l
`B-PLL
`.----.--------------~---
`~Cll
`~8
`
`Stage II: n=1
`Stage III: n=2
`Stage IV: n=19
`Rai stage IV (Binet C): n=8
`Rai stage II (Binet B): n= 1
`
`Treatment regimen
`80 mg/m2 day 1 - 3 (120 min. infusion) or
`Bendamustine
`80 mg/m2 day 1 + 2 in B-CLL
`10 mg/m2 day 1 (30 min. infusion)
`375 mg/m2 week 2,3,4,5 (4 - 6 h infusion)
`before infusion: 50 mg ranitidine, 4 mg
`dimetinden,1O mg dexamethasone i.v.
`
`Mitoxantrone
`Rituximab
`
`1" repetition
`on day 36 in a
`4 week schedule
`
`25
`
`
`
`Study results
`ORR
`
`CR
`
`PR
`
`30/31 (96%)
`
`15/31 (35%)
`
`15/31 (60%)
`
`Median TIP (months)
`with median follow up of 8 months
`8
`
`4 patients achieved a CR after only 1 BMR application (B-CLL 1, lymphoplasmocytic
`lymphonia 1, follicular lymphoma 1, B-PLL 1). Responses are still durable in 21/31 pati(cid:173)
`ents (68%).
`Even lymphoma patients with a very unfavourable prognosis showed excellent responses.
`
`Toxicities
`A symptomatic reversible grade ~ or 4 hematotoxicity occurred in 4/31 pat