Use of dianhydrogalactitol and analogs or derivatives thereof in combination with platinum-containing antineoplastic agents to treat non-small-cell carcinoma of the lung and brain metastases

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer, as well as other types of malignancy, including brain metastases of NSCLC. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N 7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.

1 . A method of treating a patient with a malignancy selected from the group consisting of Stage II non-small cell lung cancer (NSCLC), Stage III NSCLC, and Stage IV NSCLC comprising the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the malignancy; and   (b) administering a therapeutically effective quantity of a platinum-based anti-neoplastic agent to the patient to treat the malignancy, wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered either subsequent to surgical resection of the NSCLC or are administered prior to surgical resection of the NSCLC to shrink the tumor prior to surgery.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1  wherein the patient has brain metastases. 
     
     
         5 . The method of  claim 1  wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered either in a single pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) dianhydrogalactitol; (ii) the platinum-based anti-neoplastic agent; and (iii) at least one pharmaceutically acceptable carrier; or in two pharmaceutical compositions: (i) a first pharmaceutical composition comprising dianhydrogalactitol and at least one pharmaceutically acceptable carrier; and (ii) a second pharmaceutical composition comprising the platinum-based anti-neoplastic agent and at least one pharmaceutically acceptable carrier. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1  wherein the patient has a wild-type p53 genotype. 
     
     
         8 . The method of  claim 1  wherein the patient has a mutated p53 genotype. 
     
     
         9 . The method of  claim 1  wherein the patient has a wild-type EGFR genotype. 
     
     
         10 . The method of  claim 1  wherein the patient has at least one mutation in a gene encoding a protein that is a target of at least one tyrosine kinase inhibitor (TKI). 
     
     
         11 . The method of  claim 1  wherein the patient is characterized by the presence of at least one additional gene in either a wild-type or mutated state encoding a product that confers resistance to therapeutic effects of at least one TKI. 
     
     
         12 . The method of  claim 11  wherein the additional gene in either a wild-type or mutated state encoding a product that confers resistance to therapeutic effects of at least one TKI is AHI-1. 
     
     
         13 . The method of  claim 12  wherein the AHI-1 gene is mutated as the result of a proviral insertion. 
     
     
         14 . The method of  claim 1  wherein the patient is characterized by a mutation in the kinase domain of ABL1 protein that is part of a BCR-ABL fusion protein that is a target of TKIs. 
     
     
         15 . The method of  claim 1  wherein the patient is characterized by a germline deletion polymorphism conferring resistance to thymidine kinase inhibitors (TKIs). 
     
     
         16 . The method of  claim 15  wherein the germline DNA deletion polymorphism is a germline DNA deletion polymorphism of 2903 bp located in the BIM gene. 
     
     
         17 . The method of  claim 16  wherein the germline DNA deletion polymorphism causes a splicing variation that leads to expression of an isoform of BIM protein that lacks a BH3 domain and thus inhibits the induction of apoptosis. 
     
     
         18 . The method of  claim 1  wherein the platinum-containing anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobapatin, heptaplatin, and lipoplatin. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18  wherein the platinum-containing anti-neoplastic agent is cisplatin. 
     
     
         21 . The method of  claim 1  wherein the dosages of dianhydrogalactitol and the platinum-containing anti-neoplastic agent are such that the dianhydrogalactitol and the platinum-containing anti-neoplastic agent act synergistically. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 21  wherein the platinum-containing anti-neoplastic agent is cisplatin. 
     
     
         24 . A pharmaceutical composition comprising:
 (a) a therapeutically effective quantity of dianhydrogalactitol;   (b) a therapeutically effective quantity of a platinum-containing anti-neoplastic agent; and   (c) optionally, at least one pharmaceutically acceptable carrier.   
     
     
         25 . The pharmaceutical composition of  claim 24  wherein the pharmaceutical composition is formulated for treatment of a malignancy selected from the group consisting of Stage II non-small cell lung cancer (NSCLC), Stage III NSCLC, and Stage IV NSCLC. 
     
     
         26 . The pharmaceutical composition of  claim 24  wherein the pharmaceutical composition is formulated for treatment of a malignancy selected from the group consisting of Stage II non-small cell lung cancer (NSCLC), Stage III NSCLC, and Stage IV NSCLC wherein metastasis to the brain has occurred. 
     
     
         27 . The pharmaceutical composition of  claim 24  wherein the dosages of dianhydrogalactitol and the platinum-containing anti-neoplastic agent are such that the dianhydrogalactitol and the platinum-containing anti-neoplastic agent act synergistically. 
     
     
         28 . The pharmaceutical composition of  claim 24  wherein the platinum-containing anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobapatin, heptaplatin, and lipoplatin. 
     
     
         29 . (canceled) 
     
     
         30 . The pharmaceutical composition of  claim 28  wherein the platinum-containing anti-neoplastic agent is cisplatin. 
     
     
         31 . The pharmaceutical composition of  claim 24  wherein the composition comprises at least one pharmaceutically acceptable carrier, and wherein the pharmaceutically acceptable carrier is selected from the group consisting of aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, and isotonic and/or absorption delaying agents. 
     
     
         32 . The pharmaceutical composition of  claim 24  wherein the pharmaceutical composition is formulated for parenteral administration. 
     
     
         33 . The pharmaceutical composition of  claim 24  wherein the pharmaceutical composition further comprises at least one p53 mimetic that promotes p53 function. 
     
     
         34 . The pharmaceutical composition of  claim 33  wherein the p53 mimetic that promotes p53 function is selected from the group consisting of:
 (i) N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride hydrate) (CP-31398); 
 (ii) a compound of Formula (P-1): 
 
       
         
           
           
               
               
           
         
       
       wherein:
  (A) R 1  and R 4  are each independently selected from the group consisting of amino, cyano, nitro, carboxyl, halo, hydroxyl, SO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 8  alkoxyl, C 1 -C 11  alkoxyalkyl, C 1 -C 6  alkylamino, and C 1 -C 6  aminoalkyl; 
  (B) R 2  and R 3  are each independently selected from the group consisting of CH and N; 
  (C) R 5  is CH or O; 
  (D) R 6  is selected from the group consisting of halogen, cyano, nitro, C 1 -C 10  branched or unbranched, saturated or unsaturated alkyl, C 1 -C 10  branched or unbranched alkoxy, C 1 -C 10  branched or unbranched acyl, C 1 -C 10  branched or unbranched acyloxy, C 1 -C 10  branched or unbranched alkylthio, aminosulfonyl, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl, and heteroaryloxy; 
  (E) R 7  is selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1 -C 10  branched or unbranched, saturated or unsaturated alkyl, C 1 -C 10  branched or unbranched alkoxy, C 1 -C 10  branched or unbranched acyl, C 1 -C 10  branched or unbranched acyloxy, C 1 -C 10  branched or unbranched alkylthio, aminosulfonyl, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl, and heteroaryloxy; 
  (F) R 8  is selected from the group consisting of nitro, hydroxy, and carboxyl; and 
  (G) R 9  is methyl; or 
 
       a pharmaceutically acceptable ester or salt thereof; and
 (iii) a compound having a stable, internally constrained protein secondary structure, wherein the compound is of Formula (P-2): 
 
       
         
           
           
               
               
           
         
       
       wherein:
  (A) B is C(R 1 ) 2 , O, S, or NR 1 ; 
  (B) each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
  (C) R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 , wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula (P-2(a)): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 °(1) R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; a targeting moiety; or a tag; or; —(CH 2 ) 0-1 N(R 5 ) 2 , wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; 
 °(2) m′ is zero or any number; 
 °(3) each b is independently 1 or 2; and 
 °(4) c is 1 or 2; 
  (D) R 3  is hydrogen; an alkyl; an alkenyl; a cycloalkyl; a heterocyclyl; 
 an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula (P-2(b)): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 °(1) R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl; an aryl, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; 
 °(2) m″ is zero or any number; and 
 °(3) each d is 1 or 2; 
  (E) each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
  (F) m, n′, and n″ are each independently 0, 1, 2, 3, or 4, wherein the sum of m, n′, and n″ is from 2 to 6; 
  (G) m′″ is 0 or 1; 
  (H) a is 1 or 2; 
  (I) each o is independently 1 or 2; and 
  (J) p is 1 or 2; 
 
       wherein at least one of the following conditions is met: (i) m is 1, 2, 3, or 4 and at least one o is 2; (ii) p is 2; (iii) m′″ is 1 and a is 2; (iv) R 2  is a beta amino acid; (v) R 2  is a moiety of Formula (P-2(a)) wherein m′ is at least 1 and at least one b is 2; (vi) R 2  is a moiety of Formula (P-2(a)) wherein c is 2; (vii) R 2  is a moiety of Formula (P-2(a)) wherein R 2′  is a beta amino acid; (viii) R 3  is a beta amino acid; (ix) R 3  is a moiety of Formula (P-2(b)) wherein m″ is at least 1 and at least one d is 2; and (x) R 3  is a moiety of Formula (P-2(b)) wherein R 3′  is a beta amino acid. 
     
     
         35 . A method for treating a patient with a malignancy selected from the group consisting of Stage II non-small cell lung cancer (NSCLC), Stage III NSCLC, and Stage IV NSCLC wherein the patient has a mutated p53 gene comprising the steps of:
 (a) determining the existence of a mutated p53 gene in the patient, wherein the mutated p53 gene affects the proliferation of the malignancy and/or the resistance of the malignancy to at least one anti-neoplastic agent;   (b) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the malignancy, wherein therapeutically effective quantity of dianhydrogalactitol is determined from results on cell lines with a mutated p53 gene;   (c) administering a therapeutically effective quantity of a platinum-based anti-neoplastic agent to the patient to treat the malignancy, wherein therapeutically effective quantity of the platinum-based anti-neoplastic agent is determined from results on cell lines with a mutated p53 gene; and   (d) optionally, administering a therapeutically effective quantity of a p53 mimetic to the patient to treat the malignancy.   
     
     
         36 . The method of  claim 35 , wherein the existence of the mutated p53 gene in the patient is determined by a method selected from the group consisting of gene sequencing, restriction fragment length polymorphism, and determining whether p53 in a cell sample from the patient binds to a pGL3 vector. 
     
     
         37 . (canceled) 
     
     
         37 . The method of  claim 35  wherein the method comprises the step of administering a therapeutically effective quantity of a p53 mimetic to the patient to treat the malignancy. 
     
     
         38 . The method of  claim 37  wherein the p53 mimetic is selected from the group consisting of:
 (i) N′-[2-[2-(4-methoxyphenyl)ethenyl]-4-quinazolinyl]-N,N-dimethyl-1,3-propanediamine dihydrochloride hydrate) (CP-31398); 
 (ii) a compound of Formula (P-1): 
 
       
         
           
           
               
               
           
         
       
       wherein:
  (A) R 1  and R 4  are each independently selected from the group consisting of amino, cyano, nitro, carboxyl, halo, hydroxyl, SO 2 , C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 8  alkoxyl, C 1 -C 11  alkoxyalkyl, C 1 -C 6  alkylamino, and C 1 -C 6  aminoalkyl; 
  (B) R 2  and R 3  are each independently selected from the group consisting of CH and N; 
  (C) R 5  is CH or O; 
  (D) R 6  is selected from the group consisting of halogen, cyano, nitro, C 1 -C 10  branched or unbranched, saturated or unsaturated alkyl, C 1 -C 10  branched or unbranched alkoxy, C 1 -C 10  branched or unbranched acyl, C 1 -C 10  branched or unbranched acyloxy, C 1 -C 10  branched or unbranched alkylthio, aminosulfonyl, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl, and heteroaryloxy; 
  (E) R 7  is selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1 -C 10  branched or unbranched, saturated or unsaturated alkyl, C 1 -C 10  branched or unbranched alkoxy, C 1 -C 10  branched or unbranched acyl, C 1 -C 10  branched or unbranched acyloxy, C 1 -C 10  branched or unbranched alkylthio, aminosulfonyl, aryl, aroyl, aryloxy, arylsulfonyl, heteroaryl, and heteroaryloxy; 
  (F) R 8  is selected from the group consisting of nitro, hydroxy, and carboxyl; and 
  (G) R 9  is methyl; or 
 
       a pharmaceutically acceptable ester or salt thereof; and
 (iii) a compound having a stable, internally constrained protein secondary structure, wherein the compound is of Formula (P-2): 
 
       
         
           
           
               
               
           
         
       
       wherein:
  (A) B is C(R 1 ) 2 , O, S, or NR 1 ; 
  (B) each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an aryl alkyl; 
  (C) R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2 , wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula (P-2(a)): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 °(1) R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; a targeting moiety; or a tag; or; —(CH 2 ) 0-1 N(R 5 ) 2 , wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; 
 °(2) m′ is zero or any number; 
 °(3) each b is independently 1 or 2; and 
 °(4) c is 1 or 2; 
  (D) R 3  is hydrogen; an alkyl; an alkenyl; a cycloalkyl; a heterocyclyl; 
 an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula (P-2(b)): 
 
       
         
           
           
               
               
           
         
       
       wherein:
 °(1) R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl; an aryl, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; 
 °(2) m″ is zero or any number; and 
 °(3) each d is 1 or 2; 
  (E) each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
  (F) m, n′, and n″ are each independently 0, 1, 2, 3, or 4, wherein the sum of m, n′, and n″ is from 2 to 6; 
  (G) m′″ is 0 or 1; 
  (H) a is 1 or 2; 
  (I) each o is independently 1 or 2; and 
  (J) p is 1 or 2; 
 
       wherein at least one of the following conditions is met: (i) m is 1, 2, 3, or 4 and at least one o is 2; (ii) p is 2; (iii) m′″ is 1 and a is 2; (iv) R 2  is a beta amino acid; (v) R 2  is a moiety of Formula (P-2(a)) wherein m′ is at least 1 and at least one b is 2; (vi) R 2  is a moiety of Formula (P-2(a)) wherein c is 2; (vii) R 2  is a moiety of Formula (P-2(a)) wherein R 2′  is a beta amino acid; (viii) R 3  is a beta amino acid; (ix) R 3  is a moiety of Formula (P-2(b)) wherein m″ is at least 1 and at least one d is 2; and (x) R 3  is a moiety of Formula (P-2(b)) wherein R 3′  is a beta amino acid. 
     
     
         39 . The method of  claim 35  wherein the platinum-containing anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobapatin, heptaplatin, and lipoplatin. 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 39  wherein the platinum-containing anti-neoplastic agent is cisplatin. 
     
     
         42 . The method of  claim 35  wherein the dosages of dianhydrogalactitol and the platinum-containing anti-neoplastic agent are such that the dianhydrogalactitol and the platinum-containing anti-neoplastic agent act synergistically. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 42  wherein the platinum-containing anti-neoplastic agent is cisplatin.