Patent Abstract:
the invention provides a method of treatment of colorectal cancer by administration of the anti - cancer platinum drug picoplatin in conjunction with 5 - fu and leucovorin in a variety of treatment regimens .

Detailed Description:
the use of picoplatin to treat metastatic colorectal cancer will be conducted in three parts . phase 1 is a dose escalation study to identify the maximum tolerated dose ( mtd ) of picoplatin that can be administered either every two weeks or every four weeks , with 5 - fu and leucovorin ( lv ) administered every two weeks , as initial therapy for subjects with metastatic colorectal cancer who have not been previously treated for metastatic disease . phase 2 is a randomized study . in one arm of the study , picoplatin is tested at the mtd and selected schedule ( every four weeks ) combined with 5 - fu and leucovorin that are administered every two weeks , to assess safety and efficacy . in the other arm , picoplatin will be substituted for oxaliplatin in a modified folfox 6 regimen wherein the 100 mg / m 2 oxaliplatin dose in folfox 6 has been reduced to 85 mg / m 2 , and administered every 2 weeks , so that the two agents can be compared in the context of a widely used regimen . it is believed that cancer patients can be more effectively treated with the regimen of the present invention , which employ picoplatin instead of cisplatin , carboplatin or oxaliplatin , because they will experience fewer side effects , such as neuropathy , while preferably receiving higher doses of the platinum ( pt ) drug . subjects eligible for the phase 1 study will have stage 1v colorectal cancer and will have received no systemic therapy for metastatic cancer . prior adjuvant chemotherapy with a 5 - fu - based treatment regimen not containing oxaliplatin or irinotecan is acceptable if there has been a treatment - free interval of at least 6 months . subjects are assigned centrally to treatment with picoplatin administered either every two or every four weeks and are assigned a dose of picoplatin to be given dependent on the study results to date . each patient also receives 5 - fu and leucovorin therapy every two weeks . cohorts of 3 subjects receive their assigned dose of picoplatin and leucovorin and 5 - fu according to the following schedule : day 1 : picoplatin , assigned dosage , as a 2 - hour infusion , given either every cycle of 5 - fu and leucovorin ( q 2 weeks , schedule a ) or with every other cycle of 5 - fu and leucovorin ( q 4 weeks , schedule b ). leucovorin , 400 mg / m 2 in d5w ( water - 5 % dextrose ), will be administered as a 2 hour infusion , either alone or , if the patient is to receive picoplatin , at the same time as picoplatin in separate bags using a y - line . the leucovorin (± picoplatin ) will be followed by a 5 - fu bolus = 400 mg / m 2 and then by 5 - fu , 2 , 400 mg / m 2 in d5w administered as a 46 hour continuous infusion . subjects in phase 1 are centrally assigned to one of two schedules of picoplatin . the first cohort of q 2 week ( schedule a ) subjects are treated with picoplatin at a dosage of 45 mg / m 2 , every cycle , q 2 weeks . subsequent sequential cohorts of subjects assigned to this schedule receive picoplatin at dose levels increasing by 15 mg / m 2 if treatment is well tolerated to 75 mg / m 2 and then by 5 mg / m 2 to 90 mg / m 2 , and finally by 15 mg / m 2 to 135 mg / m 2 until unacceptable dose - limiting toxicity ( dlt ) establishes the mtd . the mtd is defined as the dose of picoplatin below the dose at which at least one third of at least 6 subjects experience a dlt . tolerance data from only the first 4 weeks of treatment is used to determine the mtd . thus , data following the first two doses of picoplatin in the q 2 week ( schedule a ) subjects and following only the first dose of picoplatin in the q 4 week ( schedule b ) subjects are considered . the first cohort of q 4 week ( schedule b ) subjects will be treated with picoplatin at a dosage of 60 mg / m 2 , every other cycle , q 4 weeks . subsequent sequential cohorts of subjects assigned to this schedule will receive picoplatin at dose levels increasing by 30 mg / mr 2 if treatment is well tolerated and until unacceptable dose - limiting toxicity ( dlt ) establishes the mtd . depending on the pattern and severity of toxicity observed , additional intermediate dose levels of either schedule of picoplatin administration may be studied . within each schedule , the cohort size is 3 subjects , and is expanded to 6 - 10 subjects if a dlt is observed . within each cohort of each schedule , one patient is treated initially ; if no dlt is observed within the following 4 weeks ( 2 drug cycles ), the remaining two subjects may be treated . if a dlt is observed in the first patient within a cohort , whether or not to proceed with enrollment of additional subjects in the cohort will be determined on a case - by - case basis . all subjects within a q 2 week ( schedule a ) cohort will have completed 2 cycles ( a cycle = the 2 - day treatment regimen and an additional 12 - day follow - up period ) prior to escalating the dose in the next cohort of subjects . all subjects within a q 4 week ( schedule b ) cohort will have completed 1 cycle of the 2 - day treatment regimen ( which should include 5fu / leucovorin ) and an additional 26 - day follow - up period prior to escalating the dose in the next cohort of schedule b subjects . if no dlt is observed among the 3 subjects within a cohort , picoplatin dose escalation may proceed in the next cohort of that schedule of picoplatin . if one dlt is observed , the cohort size at the specified dose and schedule of picoplatin is expanded to 6 - 10 subjects . additional subjects may be entered at any dosage level and schedule below the dose at which 2 of 6 have dlt to obtain additional safety or efficacy data . the dose of the phase 2 component of this study is selected based on the dose intensity of picoplatin achieved on each dose and schedule , the number of cycles tolerated and a subjective assessment of the tolerability and safety profile of each dose and schedule and a preliminary assessment of response rate in accord with phase 1 . the schedule for phase 2 is selected as schedule b , the q 4 week schedule . the subjects ( approximately 100 with metastatic crc , at about 25 clinical sites ) are randomized to the modified folfox 6 6 or to folpi - 150 . picoplatin 150 mg / m 2 , is administered with every alternate cycle of 5 - fu and leucovorin ( q 4 weeks , schedule b ) as a 2 hour infusion . leucovorin ( 400 mg / m 2 in d5w ) is administered every 2 weeks as a 2 - hour infusion , either alone , or given at the same time as the picoplatin in a separate bag using a y - line . the administration of leucovorin ± picoplatin is followed by a 5 - fu bolus of 400 mg / m 2 and then by 5 - fu , 2400 mg / m 2 in d5w administered as a 46 hour continuous infusion . oxaliplatin 85 mg / m 2 , as a 2 - hour infusion is administered every 2 weeks . leucovorin ( 400 mg / m 2 in d5w ) is administered every 2 weeks as a 2 - hour infusion . oxaliplatin is given at the same time as the leucovorin in a separate bag using a y - line . the administration of leucovorin + oxaliplatin is followed by a 5 - fu bolus of 400 mg / m 2 and then by 5 - fu , 2400 mg / m 2 in d5w administered as a 46 hour continuous infusion . neuropathy assessment is performed at baseline and after every two cycles of therapy ( approximately every month ) by an independent neurologist . the subject and the neurologist are not informed whether the platinum infused is oxaliplatin or picoplatin . this assessment by the neurologist is used to determine the incidence of grade 2 or greater peripheral neuropathy . in phase 2 , for the purpose of determining toxicity for dose reduction or study drug discontinuation , the treating physician performs a neurological assessment using the nci ctcae . these ctcae criteria are used to determine the need to dose reduce prior to each cycle . the assessment of the neurologist is used for determination of the safety endpoint , the incidence of neuropathy , and is performed independently every other cycle using the protocol - specified neuropathy scale , but is not be used for dose modification . for all subjects , hematology and serum chemistry laboratory studies are obtained prior to each treatment cycle . treatment cycles ( 5 - fu and leucovorin ± picoplatin or oxaliplatin depending on schedule ) are repeated every 2 weeks , but may be delayed up to 2 weeks while awaiting recovery of clinical or laboratory abnormalities . data from all cycles of treatment and cumulative toxicity are assessed for safety analysis . tumor evaluations will be done at baseline and after every 4th treatment of 5 - fu / leucovorin ( every 8 weeks , unless doses have been delayed ) on study . the efficacy endpoint will include objective response rate according to recist criteria . 26 duration of response , time to progression , progression - free survival , and overall survival are also evaluated . the demographics and study treatments are summarized in table 1a , 1b and 1c , below : a picoplatin : over 2 hours 150 mg / m 2 ; oxaliplatin : 85 mg / m 2 , over 2 hours ; lv : 400 mg / m 2 over 2 hours ( concurrent with picoplatin when given or oxaliplatin ) followed by 5 - fu : 400 mg / m 2 bolus and then 2400 mg / m 2 over 46 hours . all subjects continue cycles every two weeks until progression or discontinuation of study drug due to toxicity . picoplatin was generally tolerated in combination with other myelosuppressive chemotherapeutic agents in previous phase 1 studies at doses of 120 - 150 mg / m 2 administered every 3 weeks , i . e ., doses equivalent to 80 - 100 mg / m 2 every 2 weeks or 160 - 200 mg / m 2 administered every 4 weeks . none of these studies , however , studied picoplatin in combination with 5 - fu and leucovorin . 5 - fu / leucovorin is not generally myelotoxic and thus the doses of picoplatin selected as the initial starting doses in the dose escalation portions of the current study , i . e ., 45 mg / m 2 every two weeks and 60 mg / m 2 every four weeks , were well below the expected mtds of picoplatin administered on these schedules . investigational - site staff must use standard cytotoxic handling procedures when preparing picoplatin for administration . picoplatin is supplied as a ready - to - use formulation . the contents of the vials must be transferred to a suitable bag for administration . the compatibility of the formulation with typical infusion equipment has been assessed , and results have established compatibility with eva infusion bags , pvc infusion tubing , and polypropylene syringes when the materials are protected from light . pvc infusion bags are not recommended for administration of picoplatin . the compatibility of the formulation with typical administration sets has been assessed , and limits of acceptability have been set as 8 hours in a covered infusion bag . the product is highly sensitive to light and should not be exposed to ambient light for more than 1 hour without light protection . the bag must be protected from light during preparation and administration at the time of use . there is no preservative or bacteriostatic agent present in the picoplatin formulation . therefore , picoplatin must be transferred under aseptic conditions . the solution must be completely used or discarded within 8 hours of introduction into an infusion bag . as with all platinum complexes , contact with aluminum should be avoided . picoplatin should be administered by peripheral vein or central line ; it must not be given by the intramuscular or subcutaneous route . the starting dose will be calculated based on the body surface area from the height and weight of the patient . if the patient &# 39 ; s weight changes by more than 10 %, the treating physician must recalculate the body surface area and amend the dose . picoplatin should be administered over 2 hours . it should be administered concurrently with leucovorin , in separate bags using a y - line , when the two drugs are to be given on the same day . these two drugs have been tested and shown to be compatible when administered in this manner . subjects also received anti - emetic therapy consisting of a 5 - ht 3 receptor antagonist plus dexamethasone 30 minutes prior to a dose of picoplatin . subjects may also receive anti - emetic therapy for several days following treatment , which may include oral lorazepam , prochlorperazine , or equivalent for up to 7 days , as clinically indicated for breakthrough nausea and / or vomiting . detailed guidance for administration of 5 - fu and leucovorin are provided in the product labels . briefly , leucovorin 400 mg / m 2 iv infusion in d5w will be administered over 2 hours at the same time as picoplatin ( if picoplatin is to be given on that day ), in separate bags using a y - line , followed by a bolus of 5 - fu = 400 mg / m 2 and then by 5 - fu 2 , 400 mg / m 2 in d5w ( recommended ) administered as a 46 - hour continuous iv infusion . dose - reduction is mandatory if any of the following hematological events are observed during the previous cycle : absolute neutrophil count ( anc )& lt ; 0 . 5 × 10 9 / l for at least 5 days ; absolute neutrophil count & lt ; 1 . 0 × 10 9 / l complicated with grade ≧ 2 fever (& gt ; 38 . 5 ° c . ); platelet count & lt ; 25 × 10 9 / l ; not reaching a platelet count ≧ 100 × 10 9 / l and anc ≧ 1 . 5 × 10 9 / l by day 15 . dose reduction is also required for any treatment events involving any treatment - related grade 3 toxicity , any grade 4 toxicity , or any renal toxicity or neurotoxicities as described below . for subjects receiving picoplatin every 2 weeks , the dose reduction should be 15 mg / m 2 ; for subjects receiving picoplatin every 4 weeks the dose reduction should be 30 mg / m 2 . serum creatinine must be measured before every dose of picoplatin . for subjects with abnormal serum creatinine , the dose of picoplatin ( but not 5 - fu or leucovorin ) must be modified according to the following table 2 in phase 1 : the first time the dose of picoplatin is reduced , the bolus dose of 5 - fu should be omitted . the second time the dose of picoplatin is reduced , the infusional dose should be reduced by 600 mg / m 2 . once decreased , the reduced dose of 5 - fu should be continued ; i . e ., the dose of 5 - fu should not be subsequently increased . if the platelet count or anc count is grade 1 or 2 at day 15 in a cycle with picoplatin , and the subject receives the alternate i . e ., even numbered cycle that does not include picoplatin , the dose of 5 - fu should not be reduced at this cycle . at the next treatment cycle , the doses of picoplatin and 5 - fu should be reduced by one level . dose modifications for grade 3 or 4 non - hematological events must be made . continue treatment only once toxicity has resolved to & lt ; grade 3 . there are no dose modifications for leucovorin , unless drug sensitivity is suspected because of a temporal relationship to the time of leucovorin administration . the total picoplatin exposed in phase 1 study is summarized below on table 5 . 73 patients have been treated to date in phase 1 . in the q 2 w schedule , 1 of 6 patients showed a dlt of grade 4 thrombocytopenia and neutropenia at a picoplatin dose level of 105 mg / m 2 . the mtd for the q 2 w schedule was determined to be 85 mg / m 2 . in the q 4 w schedule , dlt was observed at 180 mg / m 2 in 2 of 6 patients . the mtd was determined to be 150 mg / m 2 . patients have received up to 24 cycles and the therapy was well tolerated . for both schedules , dose delays were primarily from neutropenia or thrombocytopenia , with increased hematological toxicity observed at higher doses as shown on table 6 , below . table 7 nonhematologic adverse events * q4w ( n = 18 ) q2w ( n = 55 ) all grade 3 / 4 all grade 3 / 4 nausea 50 % 0 56 % 2 % vomiting 22 % 0 18 % 0 anorexia 22 % 0 27 % 0 neuropathy ** 22 % 0 22 % 0 asthenia 17 % 0 36 % 2 % alopecia 17 % na 31 % na fatigue 17 % 0 7 % 0 creatinine increased *** 11 % 0 20 % 0 diarrhea 17 % 0 9 % 0 dizziness 0 0 16 % 0 stomatitis 0 0 9 % 4 % erythema 6 % 0 4 % 0 tinnitus 0 0 6 % 0 * drug - related events that occurred in more than 1 patient . ** neuropathy includes neuropathy , peripheral sensory neuropathy , neuropathy peripheral , and polyneuropathy *** when assessed and graded using lab values , 28 % on the q4w arm and 29 % on the q2w arm had grade 1 creatinine levels . 1 patient each on the q2w arm had grade 1 and grade 2 . there were no grade 3 or 4 creatinine levels . the cardiac and stomatitis events were attributed to the 5 - fu component . no grade 2 or higher neuropathy has been reported , even for four patients who have received a cumulative picoplatin dose of greater than about 900 mg / m 2 , e . g ., from about 902 - 1871 mg / m 2 , a surprising and unexpected result , particularly in view of a high incidence of moderate to severe neuropathy observed at comparable doses of oxaliplatin . picoplatin can be safely administered with fu and lv without the dose limiting neuropathy associated with folfox . in schedule a ( picoplatin q 2 week ), the preferred dosage range is about 45 - 120 mg / m 2 , e . g ., doses of 45 to 105 mg / m 2 , e . g ., 85 mg / m 2 . in schedule b ( picoplatin q 4 week ), the preferred dose can be higher , e . g ., about 120 - 210 mg / m 2 , e . g ., 120 - 180 mg / m 2 , e . g ., 150 mg / m 2 . a lower dose can also be administered , e . g ., at 45 - 90 mg / m 2 , e . g ., 60 mg / m 2 . of 73 evaluated subjects evaluated by ct scan there have been 19 confirmed partial responses and one complete response ( unconfirmed ). fifty - five of the subjects of the q2 week schedule have been evaluated and 13 partial responses were observed ( 24 %). surprisingly , some patients in cohort a1 ( 45 mg / m 2 ) showed a partial response . eighteen of 18 subjects in the q4 week schedule have been evaluated and 6 partial responses were observed ( 33 %). these results are summarized on table 8 . one patient was a 47 year - old woman with crc diagnosed 12 nov . 2007 . she was treated with laparotomy and sigmoidostomy ; four hepatic metastases were present , the largest was ( 31 mm ). after 42 weeks of folpi , repeat spiral ct showed complete response , confirmed . at that time the investigator removed the patient from study for resection of her primary lesion . some preliminary results of a phase ii study of picoplatin in combination with 5 - fluorouracil and leucovorin in potential neuropathy - sparing first line therapy against mcrc are shown below . a randomized , controlled study comparing the safety and efficacy of q4w folpi ( folpi with a 4 week dosing interval for picoplatin ) at the picoplatin maximum tolerated dose ( mtd ) of 150 mg / m 2 in comparison with an mfolfox - 6 regimen of 85 mg / m 2 oxaliplatin in combination with 5 - fu and leucovorin in patients with metastatic crc and no prior chemotherapy was carried out . efficacy was assessed by objective tumor response , progression - free survival , and overall survival . the safety of each regimen was evaluated based on the incidence of adverse effects . peripheral neuropathy was assessed in a blind study by an independent neurologist . study demographics , are shown below on table 9 . each arm of the study was comparable in size , and of comparable median age . 101 pts were randomized ( 50 to folpi , 51 to folfox ). pts have received a median of 10 , max 28 2 - week cycles of folpi and a median of 11 , max 21 2 - week cycles of folfox . median dose intensity of picoplatin = 28 mg / m 2 / wk ( range 9 - 70 ); mean relative dose intensity = 83 %. median dose intensity of oxaliplatin = 36 mg / m 2 / wk ( range 17 - 65 ); mean relative dose intensity = 92 %. neurotoxicity ( peripheral neuropathy ) was observed in 60 % of pts on folfox ( 10 % g 3 / 4 ) and 29 % of pts on folpi ( no g 3 / 4 ). most frequent g 3 / 4 aes on folpi were neutropenia ( 60 %), thrombocytopenia ( 40 %) and anemia ( 14 %). in the folfox arm , other than neuropathy , the most frequent g 3 / 4 aes were neutropenia ( 20 %) and thrombocytopenia ( 12 %). disease control ( cr + pr + sd ) was 75 % for folpi and 38 % for folfox . in the folpi arm there were 2 cr ( 4 %) and 9 pr ( 18 %). in the folfox arm there were 3 cr ( 6 %) and 11 pr ( 22 %). folpi and mfolfox - 6 deliver almost identical dose intensities of platinum . however , the q4w folpi regimen exhibits less frequent and severe neurotoxicity than does mfolfox - 6 , while producing comparable rates of partial response and stable disease . neurotoxicity is not dose - limiting for the folpi regimen , and the q4w folpi regimen has comparable non - neurological tolerability to mfolfox - 6 . although thrombocytopenia and neutropenia are more frequent and severe with folpi than with mfolfox - 6 , they are manageable , and the acute gastrointestinal toxicity of the two regimens is similar . the following references and other publications , patents and patent applications cited herein are incorporated by reference herein . 1 . jemal et al ., cancer statistics , 2004 . ca cancer j clin 54 ( 1 ): 8 - 29 , 2004 . 2 . hoff et al ., oncology ( huntingt ) 18 ( 6 ): 705 - 708 , 2004 . 3 . meyerhardt et al ., n engl j med 352 ( 5 ): 476 - 87 , 2005 . 4 . penland et al ., oncology ( huntingt ) 18 ( 6 ): 715 - 722 , 2004 . 5 . saltz et al ., n engl j med , 343 ( 13 ): 905 - 14 , 2000 . 6 . toumigand et al ., j clin oncol , 22 ( 2 ): 229 - 37 , 2004 . 7 . de gramont et al ., j clin oncol , 18 ( 16 ): 2938 - 47 , 2000 . 8 . rothenberg et al ., j clin oncol , 21 ( 11 ): 2059 - 69 , 2003 . 9 . andre et al ., n engl j med , 350 ( 23 ): 2343 - 51 , 2004 . 10 . hwang et al ., in : clinical use of oxaliplatin : case studies and roundtable discussion , editor marshall j , cmp healthcare media , oncology publishing group , manhasset , n . y . 2004 . 11 . douillard , j y , schiller , j ., eur j cancer 38 ( suppl 8 ): s25 - s31 , 2002 . 12 . beale , p , et al ., br j cancer 88 ( 7 ): 1128 - 1134 , 2003 . 13 . raynaud f i , et al ., clin cancer res 3 ( 11 ): 2063 - 2074 , 1997 . 14 . holford j , et al ., anticancer drug des 13 ( 1 ): 1 - 18 , 1998 . 15 . holford j , et al ., br j cancer 77 ( 3 ): 366 - 373 , 1998 . 16 . rogers p , et al ., eur j cancer 38 ( 12 ): 1653 - 1660 , 2002 . 17 . sharp sy , et al ., eur j cancer 38 ( 17 ): 2309 - 15 , 2002 . 18 . plasencia c , et al ., invest new drugs 22 ( 4 ): 399 - 409 , 2004 . 19 . murakami h , et al ., eur j cancer 38 ( suppl 8 ): s1 - s5 , 2002 20 . giaccone g , et al ., eur j cancer 38 ( suppl 8 ): s19 - s24 , 2002 . 21 . gore m e , et al ., eur j cancer 38 ( 18 ): 2416 - 2420 , 2002 . 22 . treat j , et al ., eur j cancer 38 ( suppl 8 ): s13 - 18 , 2002 . 23 . perez r p , et al ., eur j cancer 34 ( 10 ): 1535 - 42 , 1998 . 24 . gelmon k a , et al ., ann oncol 15 ( 7 ): 1115 - 22 , 2004 . 25 . gelmon k a , et al ., national cancer institute of canada — clinical trials group trial , ind 129 . ann oncol 14 : 543 - 548 , 2003 . 26 . therasse p , et al ., new guidelines to evaluate the response to treatment in solid tumors . european organization for research and treatment of cancer , national cancer institute of the united states , national cancer institute of canada . j natl cancer inst 92 ( 3 ): 205 - 216 , 2000 . the following patent applications are incorporated herein by reference in their entireties : u . s . ser . no . 61 / 055 , 071 , filed may 21 , 2008 ; 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