WO2018065445A1 - Administration de multiples bolus de [6r]-mthf au cours d'une chimiothérapie à base de 5-fluoro-uracile - Google Patents

Administration de multiples bolus de [6r]-mthf au cours d'une chimiothérapie à base de 5-fluoro-uracile Download PDF

Info

Publication number
WO2018065445A1
WO2018065445A1 PCT/EP2017/075153 EP2017075153W WO2018065445A1 WO 2018065445 A1 WO2018065445 A1 WO 2018065445A1 EP 2017075153 W EP2017075153 W EP 2017075153W WO 2018065445 A1 WO2018065445 A1 WO 2018065445A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
tetrahydrofolate
methylene
cancer
day
Prior art date
Application number
PCT/EP2017/075153
Other languages
English (en)
Inventor
Per Lennart Lindberg
Gunnel Elisabeth SUNDÉN
Bengt Gustavsson
Anders VEDIN
Original Assignee
Isofol Medical Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP16192366.9A external-priority patent/EP3305318A1/fr
Priority claimed from EP17187682.4A external-priority patent/EP3446703A1/fr
Application filed by Isofol Medical Ab filed Critical Isofol Medical Ab
Publication of WO2018065445A1 publication Critical patent/WO2018065445A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the treatment of solid tumors in humans such as cancer, which involves administering multiple boluses of [6R]-5,10-methylenetetrahydrofolate ([6R]- MTHF) in connection with 5-fluorouracil (5-FU) based chemotherapy.
  • [6R]-5,10-methylenetetrahydrofolate [6R]- MTHF
  • 5-fluorouracil 5-fluorouracil
  • 5-fluorouracil was first introduced in 1957, and still remains an essential part of the treatment of a wide range of solid tumors such as breast tumors, tumors of head and neck and gastrointestinal tumors.
  • 5-FU is an example of a rationally designed anticancer agent.
  • 5-FU was then synthesized as an antimetabolic agent [Heidelberger C et al. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature 1967; 179: 663- 666].
  • 5-FU the hydrogen atom in position 5 of uracil is replaced by the similar sized atom of fluorine, and 5-FU was designed to occupy the active sites of enzymes, blocking the metabolism of malignant cells.
  • the overall response rate of 5-FU alone is quite limited, reaching levels of 10-15 % [Johnston P.G., Kaye S. Capcetabine; a novel agent for the treatment of solid tumors. Anticancer Drugs 2001, 12: 639-646] and modulation strategies to increase the anticancer activity of 5-FU have been developed.
  • One of the most widely used strategies is a coadministration of Leucovorin, the calcium salt of folinic acid.
  • Leucovorin (LV) acts as a stabiliser of the ternary complex, a structure formed by 11 5,10-methylene tetrahydrofolate, the active metabolite of LV, of 2) FdUMP, the 5-FU active metabolite and of 3) Thymidylate synthase.
  • Cytotoxic chemotherapy is particularly used in patients with hormone receptor-negative patients, patients with symptomatic hormone-receptor and a rapid disease progression or a large tumor burden involving visceral organs [Wilcken N., Hornbuckle J., Ghersi D.; Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003; :CD002747].
  • 5-FU is usually combined with cyclophosphamide and methotrexate (CMF). The reponse rate is around 20 % and the OS around 20 months [Stockier M.R., Harvey V.J., Francis P. A. et al. Capecitabine versus classical cyclophosphamide,
  • 5-FU is also used for the treatment of advanced and recurring head and neck squamous cell cancer.
  • the prognosis in this patient group is generally poor with a median survival time in most studies of 6-9 months.
  • 5-FU is mainly used in combination therapies with platinum compounds. Response rates are around 30 % but the survival time remains low, around 6 months see [Clavel M., Vermorken J.B., Cognetti F. et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck.
  • CRC Colorectal cancer
  • Standard first-line adjuvant therapy of CRC includes single and combination chemotherapy with the agent 5- Fluorouracil (5-FU) [Cunningham D (2010)]. Treatment with 5-FU is usually given in combination with high doses of folate (or Leucovorin, LV) which significantly enhances the therapeutic effect of 5-FU in metastatic colorectal carcinoma.
  • 5-FU 5- Fluorouracil
  • LV needs to be converted to the active metabolite [6R]-5,10-methylenetetrahydrofolate (methyleneTHF), which subsequently forms a ternary complex with deoxyuridine monophosphate (dUMP) and the target enzyme thymidylate synthase (TS) in a reaction where dUMP is converted to dTMP [Jarmula A, Cieplak P, Montfort WR (2005) 5,10-Methylene-5,6,7,8-tetrahydrofolate conformational transitions upon binding to thymidylate synthase: molecular mechanics and continuum solvent studies. J Comput Aided Mol Des 19(2):123-136].
  • a reduced folate, fotrexorin calcium (CoFactor ® ) ((c//)-5,10,-methylenepteroyl- monoglutamate calcium salt, or [6R,S]-5,10-methylene-THF Ca salt), also known as racemic methyleneTHF, has been suggested as an alternative to LV based on the assumption that direct administration of the reduced folate methyleneTHF in place of LV might offer significant advantages with respect to clinical activity.
  • CoFactor ® is a 1:1 mixture of the two diastereoi- somers [Odin, E., Carlsson, G., Frosing, R., Gustavsson, B., Spears, CP., Larsson, P. A., 1998. Chemical stability and human plasma pharmacokinetics of reduced folates. Cancer Invest. 16, 447-455].
  • [6R]-isomer is the directly active co-substrate of TS, it was anticipated that the administration of CoFactor ® , instead of leucovorin, would be advantageous due to lower inter- and intrapatient variability regarding both clinical safety and efficacy.
  • CoFactor ® combined with 5-FU showed clinical benefit in pancreas cancer, defined as stable disease or tumor response, in 40% of patients [Saif, M.W., Makrilia N., Syrigos K., 2010. CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy. Journal of Oncology Vol. 1-5].
  • the unnatural (6S)-isomer is a partial competitive inhibitor of the natural [6R]-isomer regarding its effect as co-substrate for TS [Leary, R.P., Gaumont, Y., Kisliuk, R.L, 1974. Effects of the diastereoisomers of methylenetetrahydrofolate on the reaction catalyzed by thymidylate synthetase. Biochem. Biophys. Res. Commun. 56, 484-488].
  • Leucovorin ® or folinic acid shall both mean 5-formyl tetrahydrofolic acid, i.e. the 5-formyl derivative of tetrahydrofolic acid.
  • Folinic acid contains 2 asymmetric centers.
  • Commercially available leucovorin (LV) is composed of a 1:1 mixture of the dextroro- tary and levorotary diastereomers (d-leucovorin (c/-LV, (6R,2'S)-configuration) and /-leucovorin (/-LV, (6S,2'S)-configuration), respectively), and may also be referred to as (d,/-LV).
  • Levoleucovorin shall refer to the commercially available product which contains only the pharmacologically active levo-isomer /-LV (or LLV). In vitro, /-LV has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form c/-LV (DLV) is slowly excreted by the kidneys. Leucovorin and lev- oleucovorin have however been shown to be pharmacokinetically identical, and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, Clin Colorectal Cancer 8 200-6 (2009).
  • MTHF or methyleneTHF shall both refer to 5,10-Methylene-5,6,7,8- tetrahydrofolate.
  • racemic methyleneTHF, CoFactor ® or [6R,S]-5,10-methyleneTHF shall all refer to the 1:1 diastereomeric mixture [6R,S]-5,10-Methylene-5,6,7,8-tetrahydro- folate.
  • [6R]-5,10-MTHF shall refer to the single diastereomer, [6R]-5,10- methylenetetrahydrofolate. It is the key active metabolite of all clinically used folate-based drugs today including leucovorin and levoleucovorin and therefore does not require metabolic activation.
  • DLT Dose Limiting Toxicity
  • ⁇ At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • dU shall refer to deoxyuridine
  • the term BSA refers to Body Surface Area
  • proliferative diseases shall refer to a unifying concept that excessive proliferation of cells and turnover of cellular matrix contribute significantly to the pathogenesis of several diseases, including cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver, Crohn's disease and ulcerative colitis.
  • [6R]-5,10-methylenetetrahydrofolate [6R]-5,10- MTHF
  • [6R]-MTHF is also a metabolite of Leucovorin (LV).
  • LV Leucovorin
  • [6R]-MTHF does not need to undergo further metabolism, and may be directly involved in the formation of the FdUMP-TS ternary complex.
  • ORRs objec- tive response rates
  • [6R]-5,10-methylene-tetrahydrofolate is provided for use in a human in the treatment of solid tumors such as cancer, which treatment comprises the following steps:
  • step e) On Day 2, optionally administering one or more IV boluses each containing 5 - 1000 mg/m 2 (of BSA) [6R]-5,10-methylene-tetrahydrofolate, wherein step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition, and wherein step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 minutes between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition
  • step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 minutes between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • a method of treating a human diagnosed with a solid tumor such as cancer which method comprises:
  • step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition, and wherein step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 minutes between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • FIGURES
  • DHF dihydrofolate
  • DHFR dihydrofolate reductase
  • SHMTl serine hydroxymethyltransferase 1
  • MTHFR methylenetetrahydrofolate reductase
  • MTHFD methylenetetrahydrofolate dehydrogenase
  • MTHFS methenyltetrahydrofolate synthetase.
  • Figure 2 Results after 8 weeks' treatment from the ISO-CC-005 study: Response rates accord- ing to RECIST 1.1 in 12 first line patients and one second line patient.
  • Figure 3 Increased TS inhibition following administration of 5-FU with 30 and 60 mg/m 2 [6R]- MTHF (denoted as “6R 30” and “6R 60”) compared to 30 mg/m 2 LLV (denoted as "LLV 30") administered as 60 mg/m 2 Leucovorin (LV) which contains 50% of the pharmacologically ac- tive levo-isomer /-LV.
  • FIG. 4 Plasma dUrd levels relative to 30 mg/m 2 LLV (administered as 60 mg/m 2 Leucovorin (LV) which contains 50% of the pharmacologically active levo-isomer /-LV) following administration of 5-FU with 30 and 60 mg/m 2 [6R]-MTHF (denoted as “6R 30" and "6R 60").
  • LV Leucovorin
  • 5-Fluorouracil is possibly the most widely used anticancer drug in the world. It was discovered by Spears et al. (Spears et al., Cancer Res. 42:450 - 56 (1982)) that the therapeutic mechanism of 5-FU against murine colon cancer was complete inhibition of the DNA enzyme thymidylate synthase (TS) or abrogation of TS activity.
  • TS thymidylate synthase
  • folates specifically, tetrahydrofolates
  • dTMP pyrimidine deoxythymidine monophosphate
  • FOL - Folinic acid typically leucovorin or calcium folinate
  • Examples of frequently administered chemotherapeutic agents within first-and second line metastatic CRC include 5-FU/folate, Capecitabine, Irinotecan, Oxaliplatin, Bevacizumab, Cetuximab, and Panitumamab, used alone or in combinations, e.g. FOLFOX (i.e. LV/ 5- FU/oxaliplatin), FOLFIRI (i.e. LV/5-FU/lrinotecan), FOLFOX/bevacizumab, and 5-FU- LV/bevacizumab and/or irinotecan.
  • FOLFOX4 protocol whereby 200 mg/m 2
  • Leucovorin is administered iv over 2 hrs before 5-FU on day 1 and day 2 (5-FU 400 mg/m 2 iv bolus and then 600 mg/m 2 iv continuous infusion over 22 hrs, day 1 and day 2.
  • the protocol includes the administration of Oxaliplatin (Eloxatin) 85 mg/m 2 iv day 1, and the treatment is given Q2w x 12 cycles (see Goldberg RM et al. Pooled analysis of safety and efficacy of oxaliplatin plus 5-fluorouracil/leucovorin administrated bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006; 24:4085).
  • ORRs objective response rates
  • [6R]-5,10-methylene-tetrahydrofolate is provided for use in the treatment in a human of a solid tumor such as cancer, which treatment comprises the following steps:
  • step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition, and wherein step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 min between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • step a) is preceded by administering an anticancer drug on Day 1, either as an IV bolus or as an infusion over a period of 1-4 hours.
  • step a) is preceded by administering an anticancer drug on Day 1, either as an IV bolus or as an infusion over a period of 1-4 hours.
  • a method of treating a human diagnosed with a solid tumor such as cancer which method comprises:
  • step e) On Day 2, optionally administering one or more IV boluses each containing 5 - 1000 mg/m 2 (of BSA) [6R]-5,10-methylene-tetrahydrofolate, wherein step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition, and wherein step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 min between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • step b) is optionally repeated up to 4 times on Day 1 with an interval of 10 min - 4 hours between each repetition
  • step e) is optionally repeated up to 4 times on Day 2 with an interval of between 10 min - 60 min between each bolus being administered, and wherein all steps a) - e) are optionally repeated every 2 weeks.
  • the two or more IV boluses, administered on Day 1 each contains from 20 - 250 mg/m 2 [6R]-5,10-methylenetetrahydro- folate, such as from 30-240 mg/m 2 , such as from 30-120 mg/m 2 or such as about 30 mg/m 2 or such as about 60 mg/m 2 or such as about 120 mg/m 2 [6R]-5,10-methylenetetrahydrofolate.
  • a total of between 60 - 120 mg/m 2 [6R]-5,10-methylenetetrahydrofolate is administered over Day 1 and Day 2, optionally as two separate boluses, i.e. from between 2x30 mg/m 2 [6R]-5,10-methylenetetra- hydrofolate to 2 x 60 mg/m 2 [6R]-5,10-methylenetetrahydrofolate.
  • step a) is preceded by administering one or more anticancer drugs on Day 1, either as an IV bolus or as an infusion over a period of 1-4 hours.
  • the anticancer drug may be one or more drugs selected from Platinum Drugs such as cisplatin (CDDP), carboplatin (CBDCA) and oxaliplatin (oloxetin), Antimetabolites such as 5-fluoruracil (5-FU), capecetabine (Xeloda), gemcitabine(Gemzar ), methotrexate and pemetrexed (Alimta), Anti-tumor antibiotics, such as doxorubicin (Adriamycin), daunorubicin, actinomycin-D and mitomycin-C (MTC), Topoisomerase Inhibitors, such as irinotecan (CPT-11), topotecan (hycamtin) and etoposide (VP-16), Mitotic Inhibitors, such as irinotecan (C
  • the one or more anticancer drugs administered on Day 1 are oxaliplatin (Oloxetin) in combination with bevacizumab (Avastin).
  • the administered [6R]-5,10- methylene-tetrahydrofolate is a single diastereomer with a diastereomeric excess (d.e.) of >90% d.e., such as >93% d.e., such as >95% d.e., such as >98% d.e., such as >99% d.e., such as >99.5% d.e. or such as >99.9% d.e.
  • the administered [6R]-5,10- methylene-tetrahydrofolate is a single diastereomer with a diastereomeric excess (d.e.) of >98% d.e.
  • the solid tumor is selected from various cancer forms including colon cancer, stomach cancer, breast cancer, bowel cancer, gallbladder cancer, lung cancer (specifically adenocarcinoma), colorectal cancer (CRC) including metastatic CRC, head and neck cancer, liver cancer and pancreatic cancer.
  • lung cancer specifically adenocarcinoma
  • colorectal cancer including metastatic CRC, head and neck cancer, liver cancer and pancreatic cancer.
  • the solid tumor is selected from colon cancer and colorectal cancer.
  • the 5-FU analog or prodrug is selected from fluorinated pyrimidine bases such as capecitabine (Xeloda), ie. N4-pentyloxycarbonyl-5'- deoxy-5-fluorocytidine, tegafur, 5-fluoro-pyrimidinone, UFT, doxifluridine, 2'-deoxy-5 fluorouridine, 5'-deoxy-5-fluorouridine, l-(2'-oxopropyl)-5-FU, and alkyl-carbonyl-5-FU, BOF- A2, ftorafur(TS-l), and S-l.
  • fluorinated pyrimidine bases such as capecitabine (Xeloda), ie. N4-pentyloxycarbonyl-5'- deoxy-5-fluorocytidine, tegafur, 5-fluoro-pyrimidinone, UFT, doxifluridine, 2'-deoxy-5 fluorouridine, 5'
  • [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF) is employed as a solid form which is soluble in water, such as a lyophilisate or a salt, optionally stabilized by one or more suitable excipients and/or antioxidants such as citric acid or ascorbic acid or salt forms thereof.
  • [6 ]-5,10-methylenetetrahydrofolate is administered as one or more IV boluses, each bolus containing 5 - 1000 mg/m 2 BSA, such as 5 mg/m 2 BSA, such as 7 mg/m 2 BSA, such as 10 mg/m 2 BSA, such as 15 mg/m 2 BSA, such as 30 mg/m 2 BSA, such as 60 mg/m 2 BSA, such as 120 mg/m 2 BSA, such as 240 mg/m 2 BSA, such as 480 mg/m 2 BSA, such as 720 mg/m 2 BSA or such as 960 mg/m 2 BSA.
  • 5 mg/m 2 BSA such as 5 mg/m 2 BSA, such as 7 mg/m 2 BSA
  • 10 mg/m 2 BSA such as 15 mg/m 2 BSA
  • 30 mg/m 2 BSA such as 60 mg/m 2 BSA, such as 120 mg/m 2 BSA, such as 240 mg/m 2 BSA, such as 480 mg/m 2
  • [6R]-5,10-methylenetetrahydrofolate is administered up to 4 times on Day 1 with an interval of 20-30 min between each bolus being administered.
  • [6R]-5,10-methylenetetrahydrofolate is administered up to 4 times on Day 2 with an interval of 20-30 min between each bolus being administered.
  • [6R]-5,10-methylenetetrahydrofolate is administered up to 4 times both on Day 1 and on Day 2 with an interval of 20-30 min between each bolus being administered.
  • 5-fluorouracil is administered as one or more IV boluses, each bolus containing 10-1000 mg/m 2 BSA, such as 300 mg/m 2 BSA, such as 400 mg/m 2 BSA, such as 500 mg/m 2 BSA, such as 600 mg/m 2 BSA, such as 700 mg/m 2 BSA, such as 800 mg/m 2 BSA, such as 900 mg/m 2 BSA or such as 1000 mg/m 2 BSA.
  • a treatment cycle comprises two days. This regimen may optionally be repeated every 2 weeks for four (4) cycles, i.e. a total of eight (8) weeks.
  • Day 1 and Day 2 of the treatment cycle are separated by a period of 1-5 days, for example for monitoring purposes.
  • the treatment cycle is extended beyond Day 1 and Day 2 by a period of 1-5 days.
  • N/A not applicable
  • SP2D selected phase 2 dose
  • the time-point window for Irinotecan administration will be expanded to allow infusion times of up to 90 minutes, if necessary.
  • the administered bolus 5-FU dose should not surpass the maximum recommended daily dose of 1000 mg, regardless of the body surface area.
  • [6R]-5,10-Methylenetetrahydrofolic acid ([6 ]-MTHF) is formulated as a lyophylised powder containing 100 mg per vial (calculated as free acid).
  • 5-FU (5-fluorouracil) is formulated as injection solution. Dosing: 5-FU will be administered as i.v. bolus injections on Day 1 and Day 2 in each treatment cycle. In Arm #2 and Arm #3 of the study, 5-FU will be administered approximately 60 minutes after start of Oxaliplatin or Irinotecan administration, respectively (see description below). The treatment will be repeated every second week for four (4) cycles, i.e. eight (8) weeks.
  • Oxaliplatin is formulated as a concentrated infusion solution. Dosing: Oxaliplatin will be administered as i.v. infusion during 15 - 120minutes on Day 1 in each treatment cycle in treatment Arm #2 of the study (i.e. Cohorts #4, #5, #10, and #11) and repeated every second week for four (4) cycles. Caution will be taken regarding toxicity associated with administration that may affect rate of infusion (e.g. grade ⁇ 2 allergy, laryngopharyngeal dysesthesias, and laryngeal spasm). In such cases, rate of Oxaliplatin administration should be prolonged in following cycles according to clinical practice recommendations.
  • rate of Oxaliplatin administration should be prolonged in following cycles according to clinical practice recommendations.
  • Irinotecan is formulated as a concentrated infusion solution. Dosing: Irinotecan will be administered as i.v. infusion during 30 - 90 minutes on Day 1 in each treatment cycle in treatment Arm #3 of the study (i.e. Cohorts #6 and #7) and repeated every second week for four (4) cycles. Caution will be taken regarding early toxicity (within 24 hours) associated with Irinotecan administration, i.e. acute cholinergic syndrome, characterized by early diarrhoea, emesis, diaphoresis, abdominal cramping, and, less commonly, hyperlacrimation and rhinorrhoea. In such cases, the use of anticholinergics according to clinical practice recommendations is necessary.
  • Avastin (bevacizumab) is formulated as a concentrated infusion solution. Dosing: Bevaci- vonab is administered as i.v. infusion during 30-90 minutes on Day 1 in each treatment cycle in Treatment Arm #5 of the study (i.e. Cohorts #15) and repeated every second week for four (4) cycles.
  • Bevacizumab associated Toxicity Based on data from clinical trials in which patients primarily were treated with Bevacizumab in combination with chemotherapy, the following may be recognized as Bevacizumab associated toxicity: Most common serious adverse events: gastrointestinal perforations, haemorrhage (including pulmonary haemorrhage / haemoptysis), and arterial thromboembolism; Most common adverse events: hypertension, fatigue or as- thenia, diarrhoea, and abdominal pain.
  • ISO-CC-005 is an open clinical phase l/l l tolerability and dose definition study designed to evaluate safety and define the [6R]-MTH F dose for continued development. It evaluates four doses of [6R]-MTH F in combination with 5-FU with or without the different combinations of irinotecan or oxaliplatin and bevacizumab in patients with metastatic Colorectal Cancer using 4 different protocols:
  • the patients belong to several treatment lines ranging from first to third and even fifth lines.
  • the results from the group of patients undergoing 1 st line treatment and partially the group of patients undergoing 2 nd line treatment have now been analyzed.
  • the total dose of [6R]-MTH F was divided into two i.v. bolus injections dispensed approximately 30 and 60 minutes after the initial administration of 5-FU bolus injection (at 0 minute), respectively.
  • Plasma dUrd was determined by a method comprising liquid chromatography followed by tandem mass spectrometry broadly summarized as follows. Plasma samples were removed from -80°C freezer, trichloroacetic acid was added to the plasma, and the samples mixed and centrifuged. The supernatant was filtered in a 10 kDa molecular weight cut-off membrane filter and again centrifuged for 30 min. The solution at the bottom of the tube was then ready for LC-MS/MS analysis. Calibration samples were prepared in the same way using blank plasma samples and different internal standard concentrations. The injection volume into LC- MS/MS was 40 ⁇ . Deoxyuridine and chlorodeoxyuridine were ionized by electrospray nega- tive mode. MS parameters were optimized for maximum response of all folates. A MS/MS acquisition method (multiple reaction monitoring) was utilized. Determination of TS Inhibition.
  • the LV bolus dose of 60 mg/m 2 is the standard dose used in the so called Nordic treatment regime used widely in Scandinavia. Clinical results are similar to those obtained with other regimes when LV is administered by infusion, often 400 mg over two hours. (Gustavsson et al., (2015) Clinical Colorectal Cancer, 14: 1-10). It is interesting to note the much higher TS inhibition after administration of [6R]-MTHF ( Figure 4).
  • the ISO-CC-005 study further supports that [6R]-MTHF combined with 5-FU shows clinical benefit in colorectal cancer, defined as stable disease or partial response, in >90% of treated patients, and that by administering multiple boluses of [6R]-MTHF very high ORRs of 60-80% can be achieved.
  • the study results further support that [6R]-MTHF in combination with different forms of cytostatic agents can be safe, and that [6R]-MTHF may be efficacious and safe for these severely ill patients.
  • the Dose Limiting Toxicity (DLT) of the cytostatic agents employed in cancer treatment typically prevents further increase in dosage or strength of the treatment agent, or prevent continuation of treatment at a current dosage level. The DLT therefore often severely limits the doses of cytostatic agents which can be given to a patient.
  • the results of the ISO- CC-005 study achieved so far indicate that the toxicity of 5-FU when combined with [6R]- MTHF is reduced, compared to combinations of 5-FU with other folate adjuvants.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le traitement de tumeurs solides chez l'homme telles que le cancer, en particulier le cancer colorectal (CRC), qui consiste à administrer de multiples bolus de l'adjuvant de folate diastéréomériquement pur qu'est le [6R]-5,10-méthylènetétrahydrofolate au cours d'une chimiothérapie à base de 5-fluoro-uracile (5-FU).
PCT/EP2017/075153 2016-10-05 2017-10-04 Administration de multiples bolus de [6r]-mthf au cours d'une chimiothérapie à base de 5-fluoro-uracile WO2018065445A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP16192366.9A EP3305318A1 (fr) 2016-10-05 2016-10-05 Chimiothérapie basée sur l'acide [6r]-5,10-méthylènetétrahydrofolique dans le 5-fluorouracile
EP16192366.9 2016-10-05
EP17187682.4A EP3446703A1 (fr) 2017-08-24 2017-08-24 Administration de bolus multiples 6r]-mthf dans une chimiothérapie à base de 5-fluorouracile
EP17187682.4 2017-08-24

Publications (1)

Publication Number Publication Date
WO2018065445A1 true WO2018065445A1 (fr) 2018-04-12

Family

ID=60120023

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/075153 WO2018065445A1 (fr) 2016-10-05 2017-10-04 Administration de multiples bolus de [6r]-mthf au cours d'une chimiothérapie à base de 5-fluoro-uracile

Country Status (1)

Country Link
WO (1) WO2018065445A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018220861B2 (en) * 2017-02-14 2021-08-19 Isofol Medical Ab Methods for increasing blood plasma 2'-deoxyuridine (dUrd) and thymidylate synthase inhibition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097086A2 (fr) * 2004-04-02 2005-10-20 Adventrx Pharmaceuticals, Inc. Utilisation de 5,10-methylene tetrahydrofolate pour le traitement du cancer
WO2007064968A2 (fr) * 2005-12-02 2007-06-07 Adventrx Pharmaceuticals, Inc. Compositions pharmaceutiques stables de 5,10 methylenetetrahydrofolate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097086A2 (fr) * 2004-04-02 2005-10-20 Adventrx Pharmaceuticals, Inc. Utilisation de 5,10-methylene tetrahydrofolate pour le traitement du cancer
WO2007064968A2 (fr) * 2005-12-02 2007-06-07 Adventrx Pharmaceuticals, Inc. Compositions pharmaceutiques stables de 5,10 methylenetetrahydrofolate

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
BERG JM; TYMOCZKO JL; STRYER L: "Biochemistry", 2002, WH FREEMAN AND COMPANY, pages: 118 - 19,781-808
BREAST CANCER, Retrieved from the Internet <URL:http://www.cancerresearchuk.org/cancer-info/cancerstats/world/breast-cancer-world>
CHIA S.K.; SPEERS C.H.; D'YACHKOVA Y. ET AL.: "The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer", CANCER, vol. 110, 2007, pages 973
CLAVEL M.; VERMORKEN J.B.; COGNETTI F. ET AL.: "Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group", ANN ONCOL, vol. 5, 1994, pages 521
CUNNINGHAM D; ATKIN W; LENZ HJ; LYNCH HT; MINSKY B; NORDLINGER B ET AL.: "Colorectal cancer", LANCET, vol. 375, no. 9719, 20 March 2010 (2010-03-20), pages 1030 - 47, XP026978125, DOI: doi:10.1016/S0140-6736(10)60353-4
DAFNI U.; GRIMANI I.; XYRAFAS A. ET AL.: "Fifteen-year trends in metastatic breast cancer survival in Greece", BREAST CANCER RES TREAT, vol. 119, 2010, pages 621
EISENHAUER EA; THERASSE P; BOGAERTS J; SCHWARTZ LH; SARGENT D; FORD R ET AL.: "New response evaluation criteria in solid tumors: revised RECIST guideline", EUR J CANCER, vol. 45, no. 2, January 2009 (2009-01-01), pages 228 - 47
FERLAY J; SOERJOMATARAM I; ERVIK M; DIKSHIT R; ESER S; MATHERS C; REBELO M; PARKIN DM; FORMAN D; BRAY: "Cancer Incidence and Mortality Worldwide: IARC CancerBase", 2012, INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
FORASTIERE A.A.; METCH B.; SCHULLER D.E. ET AL.: "Randomized comparison of cisplatin plus fluorouracil and carboplatin plus 5-fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study", J CLIN ONCOL, vol. 10, 1992, pages 1245, XP002119724
FORD ET AL., CLINICAL CANCER RESEARCH, vol. 8, no. 1, 2002, pages 103 - 109
GAUMONT, Y.; KISLIUK, R.L.: "Effects of the diastereoisomers of methylenetetrahydrofolate on the reaction catalyzed by thymidylate synthetase", BIOCHEM. BIOPHYS. RES. COMMUN., vol. 56, 1974, pages 484 - 488, XP024779198, DOI: doi:10.1016/0006-291X(74)90868-7
GENNARI A.; CONTE P.; ROSSO R. ET AL.: "Survival of metastatic breast carcinoma patients over a 20-year period: a retrospective analysis based on individual patient data from six consecutive studies", CANCER, vol. 104, 2005, pages 1742
GOLDBERG RM ET AL.: "Pooled analysis of safety and efficacy of oxaliplatin plus 5-fluorouracil/leucovorin administrated bimonthly in elderly patients with colorectal cancer", J CLIN ONCOL, vol. 24, 2006, pages 4085
GUSTAVSSON, CLINICAL COLORECTAL CANCER, vol. 14, 2015, pages 1 - 10
HEIDELBERGER C ET AL.: "Fluorinated pyrimidines, a new class of tumor-inhibitory compounds", NATURE, vol. 179, 1967, pages 663 - 666, XP055063093, DOI: doi:10.1038/179663a0
JARMULA A; CIEPLAK P; MONTFORT WR: "5,10-Methylene-5,6,7,8-tetrahydrofolate conformational transitions upon binding to thymidylate synthase: molecular mechanics and continuum solvent studies", J COMPUT AIDED MOL DES, vol. 19, no. 2, 2005, pages 123 - 136, XP019248164
JEMAL A; BRAY F; CENTER MM; FERLAY J; WARD E; FORMAN D: "Global cancer statistics", CA CANCER J CLIN, vol. 61, no. 2, March 2011 (2011-03-01), pages 69 - 90
JOHNSTON P.G.; KAYE S.: "Capcetabine; a novel agent for the treatment of solid tumors", ANTICANCER DRUGS, vol. 12, 2001, pages 639 - 646
KOVOOR ET AL., CLIN COLORECTAL CANCER, vol. 8, 2009, pages 200 - 6
LANCET, vol. 365, 2005, pages 1687
LEMBERSKY BC ET AL.: "Oral uracil and tegafur plus leucovorin compared with iv 5-FU and leucovorin in stage II and III carcinoma of the colon: results from national surgical adjuvant breast and bowel project protocol C-06", J CLIN ONCOL, vol. 24, 2006, pages 2059
LONGLEY D.B. ET AL., NAT REV CANCER, 2003
LONGLEY D.B. ET AL.: "5-Fluorouracil. Mechanisms of action and clinical strategies", NAT REV CANCER, vol. 3, no. 5, May 2003 (2003-05-01), pages 330 - 8, XP008039669, DOI: doi:10.1038/nrc1074
MUHAMMAD WASIF SAIF ET AL: "Phase III Multicenter Randomized Clinical Trial to Evaluate the Safety and Efficacy of CoFactor / 5-Fluorouracil/Bevacizumab Versus Leucovorin/ 5-Fluorouracil/Bevacizumab as Initial Treatment for Metastatic Colorectal Carcinoma", CLINICAL COLORECTAL CANCER, 1 September 2006 (2006-09-01), pages 229 - 234, XP055358951, Retrieved from the Internet <URL:http://www.clinical-colorectal-cancer.com/article/S1533-0028(11)70289-4/pdf> [retrieved on 20170327] *
NELSON H; PETRELLI N; CARLIN A; COUTURE J; FLESHMAN J; GUILLEM J ET AL.: "Guidelines 2000 for colon and rectal cancer surgery", J NATL CANCER INST., vol. 93, no. 8, 18 April 2001 (2001-04-18), pages 583 - 96, XP001122098, DOI: doi:10.1093/jnci/93.8.583
ODIN, E.; CARLSSON, G.; FROSING, R.; GUSTAVSSON, B.; SPEARS, C.P.; LARSSON, P.A.: "Chemical stability and human plasma pharmacokinetics of reduced folates", CANCER INVEST, vol. 16, 1998, pages 447 - 455
PARKER WB; CHENG YC: "Metabolism and mechanism of action of 5-fluorouracil", PHARMACOL THE, vol. 48, no. 3, 1990, pages 381 - 395, XP023835373, DOI: doi:10.1016/0163-7258(90)90056-8
PETRELLI N; DOUGLASS HO JR; HERRERA L; RUSSELL D; STABLEIN DM; BRUCKNER HW ET AL.: "The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group", J CLIN ONCOL, vol. 7, no. 10, October 1989 (1989-10-01), pages 1419 - 26
PORCELLI L; ASSARAF YG; AZZARITI A; PARADISO A; JANSEN G; PETERS GJ: "The impact of folate status on the efficacy of colorectal cancer treatment", CURR DRUG METAB, vol. 12, no. 10, 2011, pages 975 - 984
RUTMAN RJ ET AL.: "Studies in 2-acetylaminofluorene carcinogenesis. III. The utilization of uracil 2-14C by preneoplastic rat liver and rat hepatoma", CANCER RES, vol. 14, 1954, pages 119 - 123
SAIF, M.W.; MAKRILIA N., SYRIGOS K.: "CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy", JOURNAL OF ONCOLOGY, vol. 1-5, 2010
SAIF, M.W; MERRITT, J; ROBBINS J; STEWART J.; SCHUPP, J: "Phase III Multicenter Randomized Clinical Trial to Evaluate the Safety and Efficacy of CoFactor@/5-Fluorouracil/Bevacizumab Versus Leucovorin/5-Fluorouracil/ Bevacizumab", INITIAL TREATMENT FOR METASTATIC COLORECTAL CARCINOMA CLINICAL COLORECTAL CANCER, vol. 6, no. 3, 2006, pages 229 - 234, XP055358951
SPEARS ET AL., CANCER RES., vol. 42, 1982, pages 450 - 56
STOCKIER M.R., HARVEY V.J., FRANCIS P.A.: "CAPECITABINE VERSUS CLASSICAL CYCLOPHOSPHAMIDE METHOTREXATE, AND FLUOROYRACIL AS FIRST-LINE CHEMOTHERAPY FOR ADVANCED BREAST CANCER", J CLIN ONCOL, vol. 29, 2011, pages 4498
THIRION P; MICHIELS S; PIGNON JP; BUYSE M; BRAUD AC; CARLSON RW; O'CONNELL M; SARGENT P; PIEDBOIS P: "Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated meta-analysis", J CLIN ONCOL, vol. 22, no. 18, 2004, pages 3766 - 3775
WETTERGREN Y; TAFLIN H; ODIN E; KODEDA K; DERWINGER K, CANCER CHEMOTHER PHARMACOL, vol. 75, 2015, pages 37 - 47
WILCKEN N.; HORNBUCKLE J.; GHERSI D.: "Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer", COCHRANE DATABASE SYST REV, 2003

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018220861B2 (en) * 2017-02-14 2021-08-19 Isofol Medical Ab Methods for increasing blood plasma 2'-deoxyuridine (dUrd) and thymidylate synthase inhibition

Similar Documents

Publication Publication Date Title
EP3446706B1 (fr) Administration de bolus multiples [6r]-mthf dans une chimiothérapie à base de 5-fluorouracile
JP2021008510A (ja) 血漿２’−デオキシウリジン（ｄＵｒｄ）の増加およびチミジル酸合成酵素阻害のための方法
EP3305318A1 (fr) Chimiothérapie basée sur l&#39;acide [6r]-5,10-méthylènetétrahydrofolique dans le 5-fluorouracile
WO2018065445A1 (fr) Administration de multiples bolus de [6r]-mthf au cours d&#39;une chimiothérapie à base de 5-fluoro-uracile
WO2018065446A1 (fr) [6r]-mthf - alternative efficace du folate dans la chimiothérapie à base de 5-fluorouracile
US20210401842A1 (en) [6R]-MTHF - an efficient folate alternative in 5-fluorouracil based chemotherapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17784911

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17784911

Country of ref document: EP

Kind code of ref document: A1