EP3033150A1 - Administration de karénitécine pour traiter un cancer avancé de l'ovaire, y compris des sous-types d'adénocarcinomes chimio-résistants et/ou mucineux - Google Patents

Administration de karénitécine pour traiter un cancer avancé de l'ovaire, y compris des sous-types d'adénocarcinomes chimio-résistants et/ou mucineux

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Publication number
EP3033150A1
EP3033150A1 EP14836702.2A EP14836702A EP3033150A1 EP 3033150 A1 EP3033150 A1 EP 3033150A1 EP 14836702 A EP14836702 A EP 14836702A EP 3033150 A1 EP3033150 A1 EP 3033150A1
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EP
European Patent Office
Prior art keywords
cancer
subject
ovarian cancer
karenitecin
platinum
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP14836702.2A
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German (de)
English (en)
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EP3033150A4 (fr
Inventor
Frederick H. Hausheer
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Crown Bioscience Inc
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BioNumerik Pharmaceuticals Inc
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Publication date
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Publication of EP3033150A1 publication Critical patent/EP3033150A1/fr
Publication of EP3033150A4 publication Critical patent/EP3033150A4/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 use of camptothecin derivatives as anti-cancer drugs. More specifically, the present invention is related to the use of the silicon-containing highly lipophilic camptothecin derivative (HLCD), Karenitecin, for the treatment of advanced ovarian cancer, including platinum/taxane cancer treating agent-resistant sub-populations and/or the mucinous adenocarcinoma-subtype of ovarian cancer.
  • HLCD highly lipophilic camptothecin derivative
  • Karenitecin platinum/taxane cancer treating agent-resistant sub-populations and/or the mucinous adenocarcinoma-subtype of ovarian cancer.
  • the present invention discloses methods for the treatment of platinum and/or taxane cancer treating agent-resistant or -refractory sub-populations and/or the mucinous adenocarcinoma-subtype of ovarian cancer subjects with the silicon-containing highly lipophilic camptothecin derivative (HLCD), Karenitecin (also known as BNP1350; cositecan; 7-[(2'-trimethylsilyl)ethyl]-20(iS) camptothecin).
  • HLCD highly lipophilic camptothecin derivative
  • Karenitecin also known as BNP1350; cositecan; 7-[(2'-trimethylsilyl)ethyl]-20(iS) camptothecin.
  • the administration of Karenitecin by intravenous (i.v.) or oral methodologies are also disclosed.
  • Karenitecin analogues including but not limited to, Germanium-substituted Karenitecin, Deuterated Karenitecin, and "flipped" E-
  • gynecological malignancies account for approximately 18.6% of all new cancer cases diagnosed and approximately 15.3% of all cancer related deaths in women worldwide.
  • ovarian carcinoma is the second most common malignancy after cervical cancer.
  • ovarian cancer accounted for 204,200 new cases and 124,700 deaths representing approximately 4.0% of new cancer cases and 4.2% of cancer related deaths in women. See, e.g., Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes. Am. J. Epidemiol.
  • Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, frequent urination, and are easily confused with other illnesses.
  • the three major histologic subtypes of ovarian carcinoma include epithelial tumors, germ cell tumors, and sex cord-stromal tumors. The majority of ovarian cancers are epithelial in origin, accounting for 80% to 90% of ovarian malignancies. See, e.g., Karlan BY, Markman MA, Eifel PJ. Ovarian cancer, peritoneal carcinoma, and fallopian tube carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer. Principles & Practice of Oncology. 9th ed.
  • the epithelial tumors arise from the surface epithelium or serosa of the ovary. In the majority of cases, malignant epithelial ovarian tumors disseminate throughout the peritoneal cavity after exfoliation of malignant cells from the surface of the ovary. Tumor spread also occurs via the lymphatics from the ovary, and spread to lymph nodes is common.
  • Ovarian cancer is a surgically-staged cancer that is staged using the International Federation of Gynecology and Obstetrics (FIGO) staging system for cancer of the ovary. See, Benedet JL, Pecorelli S, Ngan HYS, hacker NF. The FIGO Committee on Gynaecologic Oncology. Staging Classifications and Clinical Practice Guidelines of Gynaecological Cancers. 3rd ed. Elsevier; 2006:95-121. Tumors confined to the ovaries are classified as stage I. A tumor which involves one or both ovaries with pelvic extension is classified as stage II.
  • FIGO International Federation of Gynecology and Obstetrics
  • a tumor which involves one or both ovaries with microscopically-confirmed peritoneal metastases outside the pelvis and/or regional lymph nodes metastasis is classified as stage III.
  • Distant metastasis beyond the peritoneal cavity is classified as stage IV.
  • Liver capsule metastasis is considered stage III, and liver parenchymal metastasis is considered stage IV.
  • the present invention discloses and claims methods for the treatment of platinum and/or taxane cancer treating agent-resistant/-refractory sub- populations and/or the Mucinous sub-type of ovarian cancer subjects.
  • the anti-neoplastic drug cisplatin czs-diamminedichloroplatinum or "CDDP"
  • platinum based drugs including carboplatin and oxaliplatin
  • CDDP anti-neoplastic drug
  • platinum complexes are reported to act, in part, by aquation (i.e., to form reactive aqua species), some of which may predominate intracellularly, and subsequently form DNA intra-strand coordination chelation cross-links with purine bases, thereby cross-linking DNA.
  • cisplatin The currently accepted paradigm with respect to cisplatin' s mechanism of action is that the drug induces its cytotoxic properties by forming a reactive monoaquo species that reacts with the N7 nitrogen contained within the imidazole components of guanine and adenosine found in nuclear DNA to form intrastrand platinum-DNA adducts.
  • the exact mechanism of action of cisplatin is not completely understood and remains a subject of research interest within the scientific community. Thus, this mechanism is believed to work predominantly through intra-strand cross-links, and less commonly, through inter-strand cross-links, thereby disrupting the DNA structure and function, which is cytotoxic to cancer cells.
  • Platinum-resistant cancer cells are resilient to the cytotoxic actions of these agents.
  • Certain cancers exhibit intrinsic de novo natural resistance to the killing effects of platinum agents and undergo no apoptosis, necrosis or regression following initial platinum compound treatment.
  • other types of cancers exhibit cytotoxic sensitivity to platinum drugs, as evidenced by tumor regression following initial treatment, but subsequently develop an increasing level of platinum resistance, which is manifested as a reduced responsiveness and/or tumor growth following treatment with the platinum drug (i.e., "acquired resistance").
  • new cancer treating agents are continually being sought which will effectively kill tumor cells, but that are also insensitive or less susceptible to tumor-mediated drug resistance mechanisms that are observed with other platinum agents.
  • monoaquo/monohydroxy platinum complexes which is less likely to further hydrolyze to diaqua complexes.
  • cisplatin can readily form monoaquo and diaqua complexes by precipitation of chloro ligand with inorganic salts (e.g., silver nitrate, and the like).
  • the chloro ligands can be replaced by existing nucleophile (e.g. , nitrogen and sulfur electron donors, etc.) without undergoing aquation intermediates.
  • Cisplatin is relatively stable in human plasma, where a high concentration of chloride prevents aquation of cisplatin. However, once cisplatin enters a tumor cell, where a much lower concentration of chloride exists, one or both of the chloro ligands of cisplatin is displaced by water to form an aqua-active intermediate form (as shown above), which in turn can react rapidly with DNA purines (i.e., Adenine and Guanine) to form stable platinum— purine— DNA adducts.
  • DNA purines i.e., Adenine and Guanine
  • Cisplatin enters the cell through both passive diffusion and active transport.
  • the pharmacological behavior of cisplatin is in part determined by hydrolysis reactions that occur once cisplatin is inside the cell where the chloride concentration is essentially zero.
  • one chlorine ligand is replaced by a water molecule to yield an aquated version of cisplatin.
  • the aquated platinum can then react with a variety of intracellular nucleophiles.
  • Cisplatin binds to RNA more extensively than to DNA and to DNA more extensively than to protein; however, all of these reactions are thought to occur
  • 1,3-intrastrand d(GpXpG) adducts may also occur, but are readily excised by the nucleotide excision repair (NER) mechanism.
  • NER nucleotide excision repair
  • Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to cisplatin's activity.
  • replicative bypass of the platinum 1, 2-d(GpG) crosslink can occur allowing the cell to faithfully replicate its DNA in the presence of the platinum cross link, but often if this 1 ,2-intrastrand d(GpG) crosslink is not repaired, it interferes with DNA replication ultimately resulting in apoptosis.
  • HMG High Mobility Group
  • chromosomal domain proteins which are involved with transcription, replication, recombination, and DNA repair
  • HMG High Mobility Group
  • cisplatin is frequently designated as an alkylating agent, it has no alkyl group and cannot carry out alkylating reactions. Accordingly, it is more accurately classified as an alkylating-like agent.
  • the present invention discloses and claims methods for the treatment of platinum and/or taxane cancer treating agent-resistant/-refractory sub- populations and/or the Mucinous sub-type of ovarian cancer subjects.
  • Taxanes are semi-synthetically derived analogues of naturally occurring compounds derived from plants.
  • taxanes are derived from the needles and twigs of the European yew (Taxus baccata), or the bark of the Pacific yew (Taxus brevifolia).
  • the most widely known taxanes at this time are paclitaxel (Taxol) and docetaxel (Taxotere), which are widely distributed as antineoplastic agents.
  • Paclitaxel was discovered in the late 1970s, and was found to be an effective antineoplastic agent with a mechanism of action different from then-existing
  • Taxanes are recognized as effective agents in the treatment of many solid tumors which are refractory to other antineoplastic agents.
  • Paclitaxel has the molecular structure shown below as Formula (A):
  • Docetaxel is an analog of Paclitaxel, and has the molecular structure shown below as
  • Taxanes exert their biological effects on the cell microtubules and act to promote the polymerization of tubulin, a protein subunit of spindle microtubules. The end result is the inhibition of depolymerization of the microtubules, which causes the formation of stable and nonfunctional microtubules. This disrupts the dynamic equilibrium within the microtubule system, and arrests the cell cycle in the late G 2 and M phases, which inhibits cell replication. Taxanes interfere with the normal function of microtubule growth and arrests the function of microtubules by hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner.
  • Taxanes function as an anti -neoplastic agent by binding to the N-terminal 31 amino acid residues of the ⁇ -tubulin subunit in tubulin oligomers or polymers, rather than tubulin dimers.
  • anti-microtubule agents e.g., vinca alkaloids
  • submicromolar concentrations of taxanes function to decrease the lag- time and shift the dynamic equilibrium between tubulin dimers and microtubules (i.e., the hyperpolymerization of tubulin oligomers) toward microtubules assembly and stabilize the newly formed microtubules against depolymerization.
  • microtubules which are formed are highly stable, thereby inhibiting the dynamic reorganization of the microtubule network. See, e.g., Rowinsky, E.K., et ah, Taxol: The prototypic taxane, an important new class of antitumor agents. Semin. Oncol. 19:646 (1992).
  • Tubulin is the "building block" of microtubules, the resulting microtubule/taxane complex does not have the ability to disassemble.
  • the binding of taxanes inhibit the dynamic reorganization of the microtubule network. This adversely affects cell function because the shortening and lengthening of microtubules (i.e., dynamic instability) is necessary for their function as a mechanism to transport other cellular components. For example, during mitosis,
  • microtubules position the chromosomes during their replication and subsequent separation into the two daughter-cell nuclei.
  • the taxanes function to inhibit the proliferation of cells by inducing a sustained mitotic "block" at the metaphase-anaphase boundary at a much lower concentration than that required to increase microtubule polymer mass and microtubule bundle formation. See, e.g., Rao, S., et al., Direct photoaffinity labeling of tubulin with taxol. J. Natl. Cancer Inst. 84:785 (1992). It should be noted that many of the deleterious side- effects caused by the taxanes are due to the sustained mitotic "block" at the metaphase- anaphase boundary in normal (i.e., non-neoplastic cells).
  • the taxane may act as a "molecular sponge" by sequestering free tubulin, thus effectively depleting the cells supply of tubulin monomers and/or dimers. This activity may trigger the aforementioned apoptosis.
  • One common characteristic of most cancer cells is their rapid rate of cell division. In order to accommodate this, the cytoskeleton of the cancer cell undergoes extensive restructuring. Paclitaxel is an effective treatment for aggressive cancers because it adversely affects the process of cell division by preventing this restructuring. Although non-cancerous cells are also adversely affected, the rapid division rate of cancer cells make them far more susceptible to paclitaxel treatment.
  • paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called B-cell leukemia 2 (Bcl-2), thus arresting its function.
  • Bcl-2 B-cell leukemia 2
  • taxanes are complex alkaloid esters consisting of a taxane system linked to a four-member oxetan ring at positions C-4 and C-5.
  • the taxane rings of both paclitaxel and docetaxel, but not 10-deacetylbaccatin III, are linked to an ester at the C- 13 position.
  • Experimental and clinical studies have demonstrated that analogs lacking the aforementioned linkage have very little activity against mammalian tubulin.
  • the moieties at C-2' and C-3' are critical with respect to its full biological activity, specifically, for the anti-microtubule hyperpolymerization effect of taxane.
  • the C-2' -OH is of paramount importance for the activity of taxol and the Formula (I) compounds of the present invention, and while the C-2' -OH of taxol can be "substituted" by a sufficiently strong nucleophile (see, PCT/US98/21814; page 62, line 8-27) the biological activity would be greatly diminished. See, e.g., Lataste, H., et ah, Relationship between the structures of Taxol and baccatine III derivatives and their in vitro action of the disassembly of mammalian brain. Proc. Natl. Acad. Sci. 81 :4090 (1984).
  • Taxanes are toxic compounds having a low therapeutic index which have been shown to cause a number of different toxic effects in subjects.
  • the most well-known and severe adverse effects of taxanes are neurotoxicity and hematologic toxicity, particularly anemia and severe neutropenia/thrombocytopenia. Additionally, taxanes also cause hypersensitivity reactions in a large percentage of subjects; gastrointestinal effects ⁇ e.g., nausea, diarrhea and vomiting); alopecia; anemia; and various other deleterious physiological effects, even at the recommended dosages.
  • Taxane medicaments include, in a non-limiting manner, docetaxel or paclitaxel (including the commercially-available paclitaxel derivatives Taxol and Abraxane), polyglutamylated forms of paclitaxel ⁇ e.g., Xyotax), liposomal paclitaxel ⁇ e.g., Tocosol), and analogs and derivatives thereof.
  • the present patent application discloses and claims new and novel inventions which have been derived from the results of a multi-center, multi-national, randomized, open-label, active-controlled, Phase III human clinical study to compare and evaluate the safety and efficacy of the silicon-containing highly lipophilic camptothecin derivative (HLCD) cancer treating drug Karenitecin (also known as BNP1350; cositecan; 7-[(2'-trimethylsilyl)ethyl]- 20(5) camptothecin) with that of the camptothecin-analogue chemotherapeutic drug
  • HLCD highly lipophilic camptothecin derivative
  • Topotecan wherein the drugs were administered to the trial subjects as a single, daily intravenous dose of either Karenitecin or Topotecan - [Karenitecin 1.0 mg/m /day x 5 (first 5 consecutive days per cycle) in a 60 minute i.v. infusion or Topotecan 1.5 mg/m /day x 5 (first 5 consecutive days per cycle) in a 30 minute i.v.
  • the present patent application discloses and claims new and novel inventions which have been derived from the results of a Phase I clinical trial performed to determine the maximum tolerated dose (MTD) of oral Karenitecin in subjects given in a dose-escalated manner (starting at 0.5 mg/m ) and administered 3 -times per week (MWF or TTS) for 3 consecutive weeks followed by a one -week treatment rest.
  • MTD maximum tolerated dose
  • Such Phase I clinical trial of oral Karenitecin is sometimes referred to herein as the "Oral Karenitecin Phase I Trial”.
  • PFS Progression Free Survival
  • PD radiographically-documented Progressive Disease
  • RECIST radiographical objective disease
  • OS Overall Survival
  • NCI- CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • neutropenia including febrile neutropenia
  • thrombocytopenia defined as the proportion of subjects who experience > grade 3 thrombocytopenia based on NCI-CTCAE criteria at any time post-baseline after receiving study treatment.
  • the probability for cure for subjects with advanced ovarian cancer had previously been thought to be remote (with palliation and optimizing the quality of life being the primary treatment goals).
  • the observations in the Karenitecin Phase III Trial regarding increases in the mean and median number of treatment cycles able to be administered to subjects, as well as observations regarding an improved drug administration safety profile, may improve the probability of advanced ovarian cancer being able to be treated as a chronic disease or even for a cure.
  • a method for the treatment of platinum and/or taxane -refractory or -resistant advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, which is platinum and/or taxane-refractory or - resistant.
  • a method for the treatment of a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents.
  • a method for increasing the time period of Progression Free Survival (PFS) in a subject having advanced ovarian cancer , including mucinous adenocarcinoma-subtype of ovarian cancer is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a an increase in the time period of Progression Free Survival (PFS) in the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer.
  • a method for increasing the time period of Progression Free Survival (PFS) in a subject having the mucinous adenocarcinoma- subtype of ovarian cancer and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having the mucinous adenocarcinoma-subtype of ovarian cancer and/or is refractory or resistant to platinum and/or taxane cancer treating agents.
  • PFS Progression Free Survival
  • a method for increasing the time period of Progression Free Survival (PFS) while concomitantly reducing cancer treating agent- related toxicities to a subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v.
  • the various cancer treating agent-related toxicities include, but are not limited to, hematological, gastrointestinal, anorexia, and other cancer treating agent-related toxicities.
  • a method for treating a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, while also concomitantly reducing the occurrence of cancer treating agent-induced anemia, thrombocytopenia, and/or neutropenia is disclosed, wherein the method is comprised of the oral and/or i.v.
  • ovarian cancer in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer is disclosed, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, while concomitantly reducing the occurrence or grade of occurrence of cancer treating agent-induced anemia, thrombocytopenia, and/or neutropenia.
  • a method for treating a subject having advanced ovarian cancer while reducing cumulative hematological toxicity to the subject undergoing treatment including treatment of a subject having the mucinous subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents.
  • a method for increasing the total number of cancer treating agent treatment cycles and/or the length of each individual cancer treating cycle in a subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v.
  • a method for increasing the platinum- free time interval, the time that elapses after the completion of the initial platinum-based therapy, in a subject having relapsed advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having relapsed advanced ovarian cancer.
  • a method for increasing the platinum-free time interval, the time that elapses after the completion of the initial platinum- based therapy, in a subject having relapsed advanced ovarian cancer which is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to a subject having relapsed advanced ovarian cancer which is refractory or resistant to platinum and/or taxane cancer treating agents.
  • a method for increasing the platinum-free time interval, the time that elapses after the completion of the initial platinum- based therapy, in a subject having a relapse of advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v.
  • a method to decrease the CA-125 marker levels in a subject having advanced ovarian cancer, including the mucinous adenocarcinoma- subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the method is comprised of the oral and/or i.v. administration of Karenitecin in an amount sufficient to decrease the CA-125 marker levels in the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents.
  • a composition for the treatment of advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the composition is comprised of Karenitecin and a specific protein-targeting monoclonal antibody (e.g., T-DM1 ; inotuzumar) attached to or conjugated with the Karenitecin, which is administered (via oral or i.v.
  • a specific protein-targeting monoclonal antibody e.g., T-DM1 ; inotuzumar
  • ovarian cancer means) concomitantly or in series in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents.
  • a composition for the treatment of advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents
  • the composition is comprised of Karenitecin (administered via oral and/or i.v. means) and one or more cancer treating agents administered concomitantly or in series in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents.
  • the cancer treating agents are selected from the group consisting of: fluropyrimidines; pyrimidine nucleosides; purine nucleosides; anti- folates, platinum agents; anthracyclines/anthracenediones; epipodophyllotoxins;
  • camptothecins vinca alkaloids; taxanes; epothilones; antimicrotubule agents; alkylating agents; antimetabolites; topoisomerase inhibitors; aziridine-containing compounds; antivirals; hormones; hormonal complexes; antihormonals; enzymes, proteins, peptides and polyclonal and/or monoclonal antibodies and various other cytotoxic and cytostatic agents; as well as (i) 2,2'-dithio-bis-ethane sulfonate; (ii) the metabolite of 2,2'-dithio-bis-ethane sulfonate, known as 2-mercapto ethane sulfonate; and (iii) 2-mercapto-ethane sulfonate conjugated as a disulfide with a substituent group selected from the group consisting of: -Cys, - Homocysteine, -Cys-Gly, -Cys
  • methods allowing various treatment schedules e.g., M, W, and F; on a daily basis, etc.
  • a method which may be curative in a subject having advanced ovarian cancer, including the mucinous adenocarcinoma- subtype of ovarian cancer, and/or where the cancer is refractory or resistant to platinum and/or taxane cancer treating agents, due to the ability of the method to circumvent cancer treating agent drug-resistance in said cancer is disclosed, wherein the method is comprised of the oral and/or i.v.
  • a composition for the treatment of a subject having advanced ovarian cancer including the mucinous adenocarcinoma- subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed, wherein the composition is comprised of Karenitecin, Germanium-substituted Karenitecin, deuterated Karenitecin, and/or "flipped" E-ring Karenitecin administered by oral and/or i.v.
  • a method for treating a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, while also concomitantly reducing the occurrence or grade of occurrence of cancer treating agent-induced toxicities and/or improving the side-effect profile of cancer treating agent administration is disclosed, wherein the method is comprised of the oral and/or i.v.
  • camptothecin cancer treating agents in an amount sufficient to provide a therapeutic benefit to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or the advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, while concomitantly reducing the occurrence or grade of occurrence of cancer treating agent-induced toxicities.
  • a therapeutic benefit to the subject having one or more cancer types selected from the group consisting of: (i) advanced solid tumors; (ii) refractory or recurrent solid tumors; (iii) recurrent malignant glioma; (iv) primary malignant glioma; (v) third-line treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma; (vi) malignant melanoma; and/or (vii) relapsed or refractory non-small cell lung cancer.
  • cancer types selected from the group consisting of: (i) advanced solid tumors; (ii) refractory or recurrent solid tumors; (iii) recurrent malignant glioma; (iv) primary malignant glioma; (v) third-line treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma; (vi) malignant melanoma; and/or (vii) relapsed or refractory
  • a method to increase the progression-free survival (PFS) in a subject diagnosed with the mucinous adenocarcinoma subtype of ovarian cancer is disclosed.
  • a method to induce an increase in the progression-free survival (PFS) of a subject who is either refractory or resistant to platinum- and/or taxane- based cancer treating agents and/or had the mucinous adenocarcinoma sub-type of ovarian cancer is disclosed.
  • a method to induce a reduction of grade 3 or 4 anemia events, a reduction of grade 3 or 4 thrombocytopenia events, and a reduction of grade 4 neutropenia events in a subject during treatment with Karenitecin is disclosed.
  • a method for increasing the total number of cancer treating agent treatment cycles and/or the length of each individual cancer treating agent cycle capable of being tolerated by a subject having advanced cancer and/or where the subject's cancer is refractory or resistant to one or more cancer treating agents is disclosed, and wherein the cancer is further selected from the group consisting of: colorectal cancer, gastric cancer, esophageal cancer, cancer of the biliary tract, gallbladder cancer, breast cancer, brain cancer and cancer of the Central Nervous System, cervical cancer, ovarian cancer, endometrial cancer, vaginal cancer, uterine cancer, prostate cancer, hepatic cancer, adenocarcinoma, pancreatic cancer, lung cancer, myeloma, lymphoma, and cancers of the blood.
  • the cancer is further selected from the group consisting of: colorectal cancer, gastric cancer, esophageal cancer, cancer of the biliary tract, gallbladder cancer, breast cancer, brain cancer and cancer of the Central Nervous
  • a method to adjust the timing and dosage of Karenitecin administered to a subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is resistant or refractory to platinum and/or taxane cancer treating agents is disclosed; wherein the adjustment of the timing and dosage of Karenitecin administration is based upon cancer antigen 125 (CA-125) marker levels in said subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, with the CA-125 marker levels being measured: (i) prior to beginning the treatment regimen with Karenitecin, and (ii) during the treatment regimen with Karenitecin, with both the time interval between CA-125 marker level measurements and the amount of Karenitecin administered to said subject being dependent upon the CA-125 marker levels which measured in said subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer,
  • a patient receiving treatment with Karenitecin in the Karenitecin Phase III Trial discussed herein was observed to have a reduction in CA-125 marker levels from a high of 2072 U/ML to a low of 167 U/ML.
  • Another patient receiving treatment with Karenitecin in the Karenitecin Phase III Trial discussed herein was observed to have a reduction in CA-125 marker levels from a high of 237 U/ML to a low of 24 U/ML.
  • the adjustment of the timing and dosage of Karenitecin administered is based upon the levels of the Mucin 16 marker (MUC16) levels in a subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents is disclosed.
  • MUC16 Mucin 16 marker
  • a method to treat cancers histologically-characterized as being of the mucinous type wherein said method is comprised of the i.v. and/or oral administration of Karenitecin in an amount sufficient to provide a therapeutic benefit to the subject having one or more cancers which have been histologically-characterized as being of the mucinous type; and where the cancer is further selected from the group consisting of: colorectal cancer, gastric cancer, esophageal cancer, cancer of the biliary tract, gallbladder cancer, breast cancer, brain cancer and cancer of the Central Nervous System, cervical cancer, ovarian cancer, endometrial cancer, vaginal cancer, uterine cancer, prostate cancer, hepatic cancer, adenocarcinoma, pancreatic cancer, lung cancer, myeloma, lymphoma, and cancers of the blood.
  • the cancer is further selected from the group consisting of: colorectal cancer, gastric cancer, esophageal cancer, cancer of the biliary tract
  • a method to treat a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, and where said subject is also suffering from cancer treating agent-associated toxicity or toxicities is disclosed.
  • a method for increasing Progression Free Survival (PFS) in a subject with advanced ovarian cancer where the subject's advance ovarian cancer has been differentiated into detailed ovarian cancer histological sub-categories selected from the group consisting of: (i) the "Histological Stage: Gl-well differentiated" sub-category; (ii) the ECOG Performance Status 2" sub-category; (iii) the ECOG Performance Status 0" subcategory; (iv) the Histopathology class: Adenocarcinoma (grade >2) not otherwise specified sub-category; (v) the Histopathology class: serous adenocarcinoma" sub-category; (vi) the Histological Stage: G2 -moderately differentiated" sub-category; (vii) the FIGO Stage IV" sub-category; (viii) the FIGO Stage IV" sub-category; (ix) the FIGO Stage IIIB; "Ovary as
  • Another embodiment discloses a method for increasing Overall Survival (OS) in a subject with advanced ovarian cancer; where the subject's advance ovarian cancer has been differentiated into detailed ovarian cancer histological sub-categories selected from the group consisting of: (i) the mucinous adenocarcinoma ovarian cancer sub-category; (ii) the advanced epithelial ovarian cancer sub-category (based upon observed increase in average survival time); (iii) the FIGO Stage IV" sub-category; (iv) the Histopathology class:
  • Adenocarcinoma (grade >2) not otherwise specified; (iv) the Histological Stage: Gl-well differentiated" sub-category; and (v) the Histopathology Class: Undifferentiated carcinoma" sub-category; and where the method is comprised of the oral and/or i.v. administration of a therapeutically-effective dose of Karenitecin to the subject with advanced ovarian cancer; wherein said subject's advance ovarian cancer has been differentiated into detailed ovarian cancer histological sub-categories.
  • a method to reduce or prevent cancer treating agent-induced toxicities in a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, and where said subject is also suffering from cancer treating agent-associated toxicity or toxicities; where the method is comprised of the oral and/or i.v.
  • a therapeutically- effective dose of Karenitecin to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, and where the subject is also suffering from cancer treating agent-associated toxicity or toxicities is disclosed.
  • a method to improve the Quality of Life (QOL) in a subject having advanced ovarian cancer including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, and where said subject is also suffering from cancer treating agent-associated toxicity or toxicities; where the said method is comprised of the oral and/or i.v.
  • a therapeutically-effective dose of Karenitecin to the subject having advanced ovarian cancer, including the mucinous adenocarcinoma-subtype of ovarian cancer, and/or where the subject's advanced ovarian cancer is refractory or resistant to platinum and/or taxane cancer treating agents, and where the subject is also suffering from cancer treating agent-associated toxicity or toxicities is disclosed.
  • Figure 1 illustrates, in bar graph form, the relative five (5) year survival of subjects with Stage I to Stage IV invasive epithelial ovarian cancer.
  • Figure 2 Summary of experiments evaluating effect of BNP7787 on BNP1350-induced cytotoxicity - JHOM2B data.
  • Figure 3 Summary of experiments evaluating effect of BNP7787 on BNP1350-induced cytotoxicity - OMC3 data.
  • adenocarcinoma refers to a cancer that originates in glandular tissue.
  • Glandular tissue comprises organs that synthesize a substance for release such as hormones. Glands can be divided into two general groups: (i) endocrine glands - glands that secrete their product directly onto a surface rather than through a duct, often into the blood stream and (ii) exocrine glands - glands that secrete their products via a duct, often into cavities inside the body or its outer surface.
  • the tissues or cells do not necessarily need to be part of a gland, as long as they have secretory properties.
  • Adenocarcinoma may be derived from various tissues including, but not limited to, breast, colon, lung, prostate, salivary gland, stomach, liver, gall bladder, pancreas (99% of pancreatic cancers are ductal adenocarcinomas), ovary, cervix, vagina, and uterus, as well as unknown primary adenocarcinomas.
  • Adenocarcinoma is a neoplasm which frequently presents marked difficulty in differentiating from where and from which type of glandular tissue the tumor(s) arose.
  • an adenocarcinoma identified in the lung may have had its origins (or may have metastasized) from an ovarian adenocarcinoma. Cancer for which a primary site cannot be found is called cancer of unknown primary.
  • adjuvant therapy means additional treatment of a subject with cancer given after the primary treatment or surgery to lower the risk that the cancer will come back.
  • adjuvant therapy may include treatment with cancer treating agents such as cancer treating agents, radiation therapy, hormones, cytotoxic or cytostatic agents, antibodies, and/or Karenitecin.
  • Adverse Event Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
  • An Adverse Event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
  • Adverse Drug Reaction In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions.
  • Drug-related Adverse Events are rated from grade 1 to grade 5 and relate to the severity or intensity of the event. Grade 1 is mild, grade 2 is moderate, grade 3 is severe, grade 4 is life threatening, and grade 5 results in death.
  • Serious Adverse Event or Adverse Drug Reaction A Serious Adverse Event (experience or reaction) is any untoward medical occurrence that at any dose:
  • cancer refers to all known forms of cancer including, solid forms of histopatho logically classified forms of cancer (e.g., those that form tumors), lymphomas, and non-solid tumors e.g., leukemias.
  • an amount sufficient to provide a therapeutic benefit” or “a therapeutically-effective” amount” in reference to the medicaments, compounds, or compositions of the instant invention refers to the administered dosage that is sufficient to induce a desired biological, pharmacological, or therapeutic outcome(s) in a subject suffering from one or more types of cellular metabolic anomalies or other pathophysiological conditions, including cancer.
  • such outcome(s) can include: (i) cure or remission of previously observed cancer(s); (ii) shrinkage of tumor size; (iii) reduction in the number of tumors; (iv) delay or prevention in the growth or reappearance of cancer; (v) selectively sensitizing cancer cells to the activity of the anti-cancer agents; (vi) restoring or increasing apoptotic effects or sensitivity in tumor cells; and/or (vii) increasing the time of survival of the subject, alone or while concurrently experiencing reduction, prevention, mitigation, delay, shortening the time to resolution of, alleviation of the signs or symptoms of the incidence or occurrence of an expected side- effects), toxicity, disorder or condition, or any other untoward alteration in the subject.
  • cancer refers to all known forms of cancer including, solid forms of cancer (e.g., tumors), lymphomas, and leukemias.
  • cancer treating agent refers to medicament(s) that reduces, prevents, mitigates, limits, and/or delays the growth of metastases or neoplasms, or kills neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
  • the cancer treating agents of the present invention include, but are not limited to: (i)
  • chemotherapeutic agents e.g., fluropyrimidines, pyrimidine nucleosides, purine nucleosides, anti-folates, platinum agents, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, vinca alkaloids, taxanes, epothilones, antimicrotubule agents, alkylating agents, antimetabolites, topoisomerase inhibitors, and the like); (ii) hormones, hormonal complexes, and antihormonals (e.g., interleukins, interferons, leuprolide, pegasparaginase, and the like); (iii) enzymes, proteins, and peptides; antivirals (e.g., acyclovir, zidovudine, and the like); (iv) cytotoxic agents and cytostatic agents; (v) polyclonal and monoclonal antibodies, including agents selected from the group consisting of crizotin
  • cancer treating agent regimen(s) or “cancer treating agent therapy” or “chemotherapy treatment cycle”, or “treatment cycle” or “cancer treating agent cycle”, or cancer treating agent treatment cycle” refer to treatment using one or more of the cancer treating agents, mentioned above, with or without the use of the sulfur-containing small molecules of the present invention.
  • cancer treatment agent(s) or “cancer treatment drug(s)”or “cancer treatment composition(s)” or “chemotherapeutic agent(s)” refer to a medicament or medicaments that reduces, prevents, mitigates, limits, and/or delays the growth of metastases or neoplasms, or kills neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
  • the cancer treating agents of the present invention include, but are not limited to: (i) chemotherapeutic agents (e.g., fluropyrimidines, pyrimidine nucleosides, purine nucleosides, anti-folates, platinum agents,
  • chemotherapeutic agents e.g., fluropyrimidines, pyrimidine nucleosides, purine nucleosides, anti-folates, platinum agents
  • anthracyclines/anthracenediones epipodophyllotoxins, camptothecins, vinca alkaloids, taxanes, epothilones, antimicrotubule agents, alkylating agents, antimetabolites,
  • topoisomerase inhibitors and the like.
  • hormones hormones, hormonal complexes, and the like.
  • antihormonals e.g., interleukins, interferons, leuprolide, pegasparaginase, and the like
  • enzymes, proteins, and peptides e.g., acyclovir, zidovudine, and the like
  • cytotoxic agents and cytostatic agents e.g., polyclonal and monoclonal antibodies, including agents selected from the group consisting of crizotinib, gefitinib, erlotinib, cetuximab, afatinib, dacomitinib, ramucirumab, necitumumab, lenvatinib, palbociclib, alectinib, zybrestat, tecemotide, obinutuzumab (GAlOl), AZD9291 , CO-1686, vintafolide, CRLXlOl , ipilimumab, yervoy, nivolumab
  • Cancer treatment agents of the present invention include, but are not limited to: (i) chemotherapeutic agents (e.g., fluropyrimidines, pyrimidine nucleosides, purine nucleosides, anti-folates, platinum agents, anthracyclines/anthracenediones, epipodophyllotoxins, camptothecins, vinca alkaloids, taxanes, epothilones, antimicrotubule agents, alkylating agents, antimetabolites, topoisomerase inhibitors, and the like); (ii) hormones, hormonal complexes, and antihormonals (e.g., interleukins, interferons, leuprolide, pegasparaginase, and the like); (iii) enzymes, proteins, and peptides; antivirals (e.g., acyclovir, zidovudine, and the like); (iv) cytotoxic agents, cytostatic agents; (v) polyclonal and mono
  • cancer treating agent effect or “chemotherapeutic effect” or “cytotoxic or cytostatic activities” refer to the ability of an
  • agent/medicament/composition to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms, or kill neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
  • cancer treating agent cycle or “cancer treating agent regimen(s)” refer to treatment using the above-mentioned cancer treating agents with or without the compounds of the present invention.
  • cancer treatment agent effect refers to the ability of an agent/medicament/composition to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms, or kill neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
  • chemoenhancing agent(s) refers to agents that enhance or improve the cancer treating ability or performance of cancer treating agents.
  • the term chemoenhancing agents includes: (i) 2,2'-dithio-bis-ethane sulfonate, including disodium 2,2'- dithio-bis-ethane sulfonate; (ii) the metabolite of 2,2'-dithio-bis-ethane sulfonate, known as 2- mercapto ethane sulfonate; and (iii) 2-mercapto-ethane sulfonate conjugated as a disulfide with a substituent group selected from the group consisting of: -Cys, -Homocysteine, -Cys- Gly, -Cys-Glu, -Cys-Glu-Gly, -Cys-Homocysteine, -Homocysteine-Gly,
  • the term "cumulative treatment-related toxicity” refers to cumulative and/or irreversible toxicities that frequently occur with repeated cycles of cancer treating agents. Recognition of recurrent ovarian cancer as a disease with significant secondary responses and remissions has led to an increase in the need for oncologists to plan for the long-term therapy of patients. However, many of the currently available front-line and salvage agents used in advanced ovarian cancer are associated with cumulative and/or irreversible toxicities that pose challenges in such long-term planning. The irreversible effects associated with some of these therapies may render patients less tolerant to subsequent treatments and lead to a cycle of diminishing treatment options with each remission and disease relapse.
  • Cumulative doxorubicin and paclitaxel exposure must also be monitored to minimize the risk of patient morbidity due to cardiotoxicity and neuropathy, respectively.
  • Gemcitabine shares many overlapping toxicities with other agents, and care must be taken during combination regimens to avoid synergy of these effects.
  • the main toxicity associated with topotecan is noncumulative, manageable myelosuppression.
  • cycle refers to the administration of a complete regimen of medicaments to the patient in need thereof in a defined time period.
  • cytostatic agents are mechanism-based agents that slow the progression of neoplastic disease and include drugs, biological agents, and radiation.
  • cytotoxic agents are any agents or processes that kill neoplastic cells and include drugs, biological agents, immunotherapy; and radiation.
  • cytotoxic is inclusive of the term “cytostatic”.
  • a therapeutically-effective amount refers to the amount that is sufficient to induce a desired biological, pharmacological, or therapeutic outcome in a subject with neoplastic disease. That result can be reduction, prevention, mitigation, delay, shortening the time to resolution of, alleviation of the signs or symptoms of, or exert a medically-beneficial effect upon the underlying pathophysiology or pathogenesis of an expected or observed side-effect, toxicity, disorder or condition, or any other desired alteration of a biological system.
  • the result will generally include or allow the reduction, prevention, mitigation, delay in the onset of, and/or attenuation of the severity of cancer treating agent-associated toxicity; an increase in the frequency and/or number of treatments; an increase in duration of cancer treating agent therapy; an increase or improvement in Progression Free Survival (PFS); an increase or improvement in Overall Survival (OS); and/or Complete Remission (CR).
  • PFS Progression Free Survival
  • OS Overall Survival
  • CR Complete Remission
  • the terms “Hazard Ratio”, “HR”, and “hazard ratio” refer to the chance of an event occurring with treatment “A” divided by the chance of the event occurring with treatment “B".
  • the hazard ratio is an expression of the hazard or chance of events occurring in one treatment arm as a ratio of the hazard of the events occurring in the other treatment arm.
  • a hazard ratio less than 1.0 means that treatment "A” is more favorable than treatment "B” in terms of the result being measured.
  • treatment “A” refers to treatment with Karenitecin and treatment “B” refers to treatment with Topotecan.
  • a hazard ratio less than 1.0 relating to Karenitecin treatment refers to a more favorable outcome in the result being measured for Karenitecin treatment in comparison to the result being measured for the treatment other than Karenitecin.
  • References to an "improvement” or “reduction” in the hazard ratio in favor of Karenitecin refer to a more favorable outcome in the result being measured for Karenitecin treatment in comparison to the result being measured for the treatment other than Karenitecin.
  • HLCD Highly Lipophilic Camptothecin Derivatives
  • maintenance therapy means the ongoing or chronic use of an agent to help lower the risk of recurrence (return of cancer) after it has disappeared or been substantially reduced or diminished or not detectable following initial therapy or surgery. Maintenance therapy also may be used for patients with advanced cancer (cancer that cannot be cured) to help keep it from growing and spreading farther.
  • mg/m represents the amount of a given compound or formulation in milligrams per square meter of the total body surface area of the subject to whom the compound or formulation is administered.
  • mucinous tumors are part of the surface epithelial- stromal tumor group of ovarian neoplasms, and account for approximately 36% of all ovarian tumors. Approximately 75% are benign, 10% are borderline, and 15% are malignant.
  • Benign mucinous tumors are typically multilocular (have several lobes), and the cysts have a smooth lining of epithelium that resembles endocervical epithelial cells with small numbers of gastrointestinal-type epithelial cells. Borderline and malignant mucinous tumors often have papillae and solid areas. There may also be hemorrhage and necrosis. It is well documented that malignancy may be only focally present in mucinous neoplasms of the ovary, so thorough sampling of the entire tumor is imperative.
  • mucinous tumors are filled with a mucus-like material, which gives them their name; this mucus is produced by mucus- secreting goblet cells, very similar to the cells lining normal intestine.
  • mucinous tumors may become very large, with some weighing as much as 25 kilograms.
  • Neoadjuvant therapy means treatment given as a first step to shrink a tumor before the main treatment or surgery is conducted.
  • Neoadjuvant therapy may include treatment with cancer treating agents such as chemotherapeutic agents, radiation therapy, hormones, cytotoxic or cytostatic agents, antibodies and/or Karenitecin.
  • Neoadjuvant therapy is intended to make later treatment or surgery easier and more likely to succeed, and reduce the consequences of a more extensive treatment or surgical technique that would be required if the tumor wasn't reduced in size or extent.
  • platinum cancer treating agents As used herein, the terms "platinum cancer treating agents" or "platinum
  • medicaments or “platinum compounds” include all compounds, compositions, and formulations which contain a platinum ligand in the structure of the molecule.
  • the valence of the platinum ligand contained therein may be platinum II or platinum IV.
  • the platinum medicaments or platinum compounds disclosed in the present invention include, in a non-limiting manner, cisplatin, oxaliplatin, carboplatin, satraplatin, and analogs and derivatives thereof.
  • platinum-free interval is defined herein as the time that elapses after the completion of the initial platinum-based therapy (including combination therapies involving the administration of platinum-based agents) in a subject having a relapse of ovarian cancer before further treatment of the subject with a platinum- and/or taxane -based
  • chemotherapeutic agent occurs.
  • platinum sensitivity is defined herein as the disease-free or treatment-free interval in a subject having ovarian cancer, after the treatment of the subject with a platinum- based cancer treatment agent, including combination therapy involving a platinum-based agent. Platinum sensitivity has emerged as an important and significant predictive indicator of response to second-line cancer treatment agent regimen.
  • protein-targeted monoclonal antibody refers to a new class of monoclonal antibodies that can effectively reach inside a cancer cell, a key goal for these important anticancer agents, as most proteins that cause or are associated with cancer are located intracellularly.
  • ESK1 monoclonal antibody
  • WT1 which is overexpressed in a range of leukemias and other cancers, including myeloma, breast, ovarian, and colorectal cancers.
  • ESK1 was engineered to mimic the functions of a T cell receptor, a key component of the immune system.
  • T cells have a receptor system that is designed to recognize proteins that are inside the cell. As intracellular proteins are degraded as part of normal cellular processes, HLA molecules carry fragments of those proteins to the cell surface. When T cells recognize certain peptides as abnormal, the T cell kills the diseased cell.
  • QOL Quality of Life
  • a maintenance or increase in a cancer subject's overall physical and mental state e.g., cognitive ability, ability to communicate and interact with others, decreased dependence upon analgesics for pain control, maintenance of ambulatory ability, maintenance of appetite and body weight (lack of cachexia), lack of or diminished feeling of "hopelessness”; continued interest in playing a role in their treatment, and other similar mental and physical states.
  • An improvement in Quality of Life includes, without limitation, improvements due to: the ease of administration of a cancer treating agent, an increase in the number of cancer treating agent treatment cycles able to be tolerated by the subject; and/or the reduced impact of the toxicity or toxic effects of a cancer treating agent.
  • the term "reducing” includes preventing and/or attenuating the overall severity of, delaying the initial onset of, and/or expediting the resolution of the acute and/or chronic pathophysiology associated with malignancy in a subject.
  • the term "refractory” refers to a subject who is suffering from an ovarian cancer which fails to respond reasonably in a favorable manner in terms of tumor shrinkage or duration of stabilization or shrinkage in response to treatment with a platinum and/or taxane cancer treatment agent(s) in the first line setting. Such patients have a best response of stable disease or their tumor(s) progress during such treatment and have a poor prognosis.
  • the term "resistant”, with respect to a platinum- and/or taxane-based cancer treatment agent, refers to a subject who is suffering from an ovarian cancer which fails to respond to treatment with a platinum and/or taxane cancer treatment agent(s) for a time of greater than 6 months or more.
  • a platinum and/or taxane cancer treatment agent(s) for a time of greater than 6 months or more.
  • subjects with a best response of Stable Disease (“SD") after a total of 6 cycles of platinum and/or taxane treatment in the first-line setting were considered to be platinum-resistant for purposes of the Karenitecin Phase III clinical trial disclosed in the present patent application.
  • taxane cancer treating agents or “taxane medicaments” or taxane chemotherapy agents” “include, in a non-limiting manner, docetaxel or paclitaxel (including the commercially-available paclitaxel derivatives Taxol® and Abraxane®), polyglutamylated forms of paclitaxel (e.g., Xyotax®), liposomal paclitaxel (e.g., Tocosol®), and analogs and derivatives thereof.
  • docetaxel or paclitaxel including the commercially-available paclitaxel derivatives Taxol® and Abraxane®
  • polyglutamylated forms of paclitaxel e.g., Xyotax®
  • liposomal paclitaxel e.g., Tocosol®
  • camptothecins of which Karenitecin (also known as BNP1350; cositecan; 7-[(2'-trimethylsilyl)ethyl]-20(S) camptothecin) is a member, have emerged as an important new class of antitumor drugs.
  • CPTs camptothecins
  • BNP1350 also known as BNP1350
  • cositecan 7-[(2'-trimethylsilyl)ethyl]-20(S) camptothecin
  • FDA United States Food and Drug Administration
  • Camptosar irinotecan HC1, Pfizer, Inc; hereinafter referred to as "CPT- 1 1"
  • CPT- 1 1 is a water-soluble CPT analog that is indicated as a component of first- line therapy in combination with 5-fluorouracil and leucovorin for subjects with metastatic carcinoma of the colon or rectum, and is also indicated for subjects with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. See, Camptosar [package insert]. New York, New York: Pfizer, Inc. (2006).
  • Hycamtin is a water-soluble CPT analogue that is indicated for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent cancer treating agent regimen(s); small cell lung cancer sensitive disease after failure of first-line cancer treating agent therapy; and stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. See, Hycamtin
  • the objective of the Karenitecin Phase III Trial was to determine the safety and efficacy of intravenous Karenitecin versus Topotecan in subjects with platinum- and/or taxane-resistant or refractory advanced ovarian cancer.
  • gynecological malignancies account for approximately 18.6% of all new cancer cases diagnosed and approximately 15.3% of all cancer related deaths in women worldwide.
  • ovarian carcinoma is the second most common malignancy after cervical cancer.
  • ovarian cancer accounted for 204,200 new cases and 124,700 deaths representing approximately 4.0% of new cancer cases and 4.2% of cancer related deaths in women. See, e.g., Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes. Am. J. Epidemiol. 159(4 ⁇ :319-335 (2004).
  • the median age of diagnosis for sporadic disease is 60 years old, although subjects with a genetic predisposition may develop this type of tumor earlier, often in their fifth decade.
  • the age-specific incidence of sporadic disease increases with age from 15-16 per 100,000 in the 40- to 44-year old age group, to a peak rate of 57 per 100,000 in the 70- to 74-year old age group. See, Id.
  • ovarian carcinoma is generally asymptomatic; the majority of subjects are diagnosed with advanced stage disease. Although much research has been conducted over the past several decades, the outcome for subjects with advanced stage ovarian cancer still remains poor, with a 5 -year survival rate ranging from less than 10% to 35% for women with stage III or IV disease.
  • Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, frequent urination, and are easily confused with other illnesses.
  • the three major histologic subtypes of ovarian carcinoma include epithelial tumors, germ cell tumors, and sex cord-stromal tumors. The majority of ovarian cancers are epithelial in origin, accounting for 80% to 90% of ovarian malignancies. See, e.g., Karlan BY, Markman MA, Eifel PJ. Ovarian cancer, peritoneal carcinoma, and fallopian tube carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer. Principles & Practice of Oncology. 9th ed.
  • the epithelial tumors arise from the surface epithelium or serosa of the ovary. In the majority of cases, malignant epithelial ovarian tumors disseminate throughout the peritoneal cavity after exfoliation of malignant cells from the surface of the ovary. Tumor spread also occurs via the lymphatics from the ovary, and spread to lymph nodes is common.
  • Ovarian cancer is a surgically-staged cancer using the International Federation of Gynecology and Obstetrics (FIGO) staging system for cancer of the ovary and uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, removal of (usually) the omentum, and pelvic (peritoneal) washing to assess any cytopathology therein. See, Benedet JL, Pecorelli S, Ngan HYS, hacker NF. The FIGO Committee on Gynecologic Oncology. Staging
  • the ovaries contain the ova and secrete the hormones that control the reproductive cycle. Removing the ovaries and the fallopian tubes greatly reduces the amount of the hormones estrogen and progesterone circulating in the body. This can halt or slow breast and ovarian cancers that need these hormones to grow.
  • FIGO stages for ovarian cancer are set forth below:
  • IA - involves one ovary; capsule intact; no tumor on ovarian surface; no
  • o IB - involves both ovaries; capsule intact; no tumor on ovarian surface;
  • o IC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings
  • Stage II - pelvic extension or implants o IIA - extension or implants onto uterus or fallopian tube; negative washings o IIB - extension or implants onto other pelvic structures; negative washings o IIC - pelvic extension or implants with positive peritoneal washings
  • FIGO histopathologic classification of epithelial ovarian neoplasms includes:
  • Epithelial ovarian tumors are then further sub-classified by grading: (a) Gx - grade cannot be assessed; (b) Gl - well differentiated; (c) G2 - moderately differentiated; and (d) G3 - poorly differentiated.
  • the prognoses of all ovarian tumors are independently affected by the following: (i) the specific stage of the cancer at time of diagnosis; (ii) the histological subtype and grading; and (iii) the volume of residual disease.
  • Other important prognostic factors include: (a) performance status; (b) the platinum-free interval; (c) response of CA-125 levels to initial treatment; and (d) progression of the disease. See, e.g., Benedet JL, Pecorelli S, Ngan HYS, hacker NF. The FIGO Committee on Gynecologic Oncology. Staging
  • Epithelial carcinoma of the ovary is often described as a "silent killer" because the majority of subjects do not present with symptoms until the disease has spread outside the ovary and pelvis (approximately 70% of subjects with epithelial cancers of the ovary present with stage III or IV disease). See, e.g., Karlan BY, Markman MA, Eifel PJ. Ovarian cancer, peritoneal carcinoma, and fallopian tube carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer. Principles & Practice of Oncology. 9th ed.
  • stage III disease has a 5 -year survival rate of approximately 35%, which is dependent on the volume of disease in the upper abdomen.
  • Patients with stage IV disease have a 5-year survival rate of less than 10%.
  • 4-year survival rates for subjects with optimal stage III disease is approximately 60%>. See, Id.
  • the relative five (5) year survival of subjects with Stage I to Stage V invasive epithelial ovarian cancer is illustrated in Figure 1.
  • ovarian cancer In most cases, the exact cause of ovarian cancer remains unknown. Epithelial ovarian cancer is a clonal disease that arises from a single cell in more than 90% of cases. Multiple genetic changes must occur in the ovarian surface epithelium (OSE) to produce malignant transformation. Repeated rupture and repair (ovulation) of the OSE provides this opportunity for genetic aberrations. Hereditary factors are implicated in approximately 5-13% of all ovarian cancers.
  • OSE ovarian surface epithelium
  • the syndromes that have been identified are: (i) the Breast-Ovarian Cancer Syndrome, linked to an inherited mutation in the BRCA1 and the BRCA2 genes (this includes site specific Ovarian Cancer Syndrome); and (ii) Type II Lynch Syndrome, which also includes colon, breast, endometrial and prostate cancer in affected individuals. See, e.g., Lynch HT, Watson P, Lynch JF, Conway TA, Fili M. Hereditary ovarian cancer.
  • a strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (FiNPCC, also known as Type II Lynch syndrome), which confers a higher risk for developing ovarian cancer.
  • Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic oophorectomy (i.e., the surgical removal of both ovaries) after completion of childbearing years.
  • Prophylactic oophorectomy significantly reduces the chances of developing both breast cancer and ovarian cancer.
  • Women with BRCA gene mutations generally also have their fallopian tubes removed at the same time (salpingo- oophorectomy), since they also have an increased risk of fallopian tube cancer.
  • Hereditary breast-ovarian cancer syndrome produce higher than normal levels of both breast cancer and ovarian cancer in genetically related families (either one individual suffered from both, or several individuals in the families suffered from one or the other disease).
  • the hereditary factors may be proven or suspected to cause the pattern of breast and ovarian cancer occurrences in the family.
  • abnormalities include: (i) deletions of 3p, 6q, 8p, and lOq; (ii) loss of heterozygosity is commonly observed on 1 lp, 13q, 16q, 17p, and 17q; (iii) mutations of the p53 oncogene occurs in over 50%> of subjects; (iv) amplification of HER2/neu gene is found in
  • VEGF vascular endothelial growth factor
  • the increased risk of developing ovarian cancer appears to be affected by several factors, including, but not limited to: (i) older women, and in those who have a first or second degree relative with the disease; (ii) hereditary forms of ovarian cancer can be caused by mutations in specific genes (most notably BRCA1, BRCA2, and genes for hereditary non- polyposis colorectal cancer); (iii) infertile women; (iv) women with endometriosis; and (v) women who have used or currently use postmenopausal estrogen replacement therapy.
  • Combination oral contraceptive pills have been shown to provide a protective factor for ovarian cancer. See, e.g., Bandera, CA. Advances in the understanding of risk factors for ovarian cancer. J Reprod Med 50(6): 399-406 (2005).
  • the relationship between use of oral contraceptives and ovarian cancer was shown in a summary of results of 45 case-control and prospective studies. Cumulatively these studies show a protective effect for ovarian cancers. Women who used oral contraceptives for 10 years had about a 60% reduction in risk of ovarian cancer, (a risk ratio 0.42 with statistically significant confidence intervals given the large study size). This was, by far, the largest epidemiological study to date on the subject (45 studies, over 20,000 women with ovarian cancer and about 80,000 controls).
  • Mucinous tumors in general, are part of the surface epithelial-stromal tumor group of ovarian neoplasms. Mucinous adenocarcinomas account for approximately 36% of all ovarian tumors. See, e.g., Smith JA and Wolf JK. Ovarian Cancer. In: Pharmacotherapy: A pathophysiologic approach, 8th ed. Dipiro JT, Talbert RL, Yee GC, et ah, -editors, New York: McGraw-Hill 2361-2375 (2008). Approximately 75% of mucinous tumors are benign, 10% are borderline, and 15% are malignant. Rarely, the tumor is seen bilaterally, with only approximately 5% of primary mucinous tumors being bilateral in nature.
  • Benign mucinous tumors are typically multilocular (have several lobes), and the cysts have a smooth lining of epithelium that resembles endocervical epithelial cells with small numbers of gastrointestinal-type epithelial cells. Borderline and malignant mucinous tumors often have papillae and solid areas. There may also be hemorrhage and necrosis. It is well documented that malignancy may be only focally present in mucinous neoplasms of the ovary, so thorough sampling of the entire tumor is imperative.
  • mucinous tumors are filled with a mucus-like material, which gives them their name; this mucus is produced by mucus- secreting goblet cells, very similar to the cells lining normal intestine.
  • mucinous tumors may become very large, with some weighing as much as 25 kilograms.
  • Cystadeno carcinomas (malignant tumors) contain a more solid growth pattern with the hallmarks of malignancy: (i) cellular atypia and stratification, (ii) loss of the normal architecture of the tissue, and (iii) necrosis.
  • the appearance can look similar to colonic cancer. Clear stromal invasion is used to differentiate borderline tumors from malignant tumors. Pseudomyxoma peritonei may present as a result of an ovarian mucinous tumor, however this is a rare cause of this condition, which is a rare condition. A more common cause of Pseudomyxoma peritonei is a mucin-producing tumor of the appendix.
  • mucinous tumors arising from the ovary usually only involve one ovary, the presence of involvement in both ovaries with a mucinous tumor suggests that the tumor may have arisen in another location, and further study is warranted.
  • the risk of mucinous tumors is significantly associated with smoking: relative risk for current smokers 2.22 (2.22 times the risk for non-smokers) and 2.02 for past smokers. Risk is also associated with smoking duration: relative risk per 20 years was 1.44. See article by Tworoger SS in Cancer March 1, 2008 using data from the Nurses Health Study.
  • mucinous adenocarcinomas comprise approximately 36% of ovarian epithelial neoplasms.
  • Mucinous carcinomas generally occur in women in the fourth to seventh decades. The mean age is 54 years.
  • the clinical presentation is similar to that of benign mucinous neoplasms, inasmuch as the majority of cases are Stage I. Rather, as these tumors can be quite large, the clinical presentation is generally that of a large pelvic or abdominal mass and abdominal distention. Recurrence and mortality in Stage I mucinous carcinoma occurs in 8-12% of cases, similar to well-staged Stage I serous carcinomas.
  • Advanced stage mucinous carcinoma (FIGO III and IV) is currently viewed as uniformly fatal, as is serous carcinoma of advanced stage. Limited data are available on FIGO Stage II tumors, as only 10% of subjects are in Stage II. Similarly, little data are available on high grade Stage I mucinous carcinomas. Occult advanced stage disease is rare compared to serous carcinoma.
  • HER2+ mucinous ovarian cancer could also be treated with an HER2+ inhibitor ⁇ e.g., trastuzumab or lapatinib) in combination with one or more cancer treating agents.
  • an HER2+ inhibitor e.g., trastuzumab or lapatinib
  • CA-125 cancer antigen 125
  • Mucin 16 is a protein that, in humans, is encoded by the MUC 16 gene. See, e.g., Yin BW, Dnistrian A, Lloyd KO. Ovarian cancer antigen CA125 is encoded by the MUC 16 mucin gene. Int. J. Cancer 98(5 :737-70 (2002). MUC 16 is a member of the mucin family glycoproteins.
  • CA-125 has been identified as a tumor maker or biomarker whose levels may be elevated in the blood sera of some subjects with specific types of cancers.
  • Mucin 16 is a membrane associated mucin that possesses a single transmembrane domain and contains 22,000 amino acid residues, making it the largest membrane associated mucin protein.
  • MUC 16 is made of three different domains; an N-terminal domain, a tandem repeat domain, and a C-terminal.
  • the N-terminal domain and tandem repeat domain are both entirely extracellular and are highly O-glycosylated.
  • the tandem repeat domain has repeating sequences high in serine, threonine, and proline residues.
  • the C-terminal domain contains multiple extracellular SEA (sea urchin sperm protein, enterokinase, and agrin) modules, a transmembrane domain, and a cytoplasmic tail.
  • SEA extracellular SEA
  • CA-125 is the most frequently used biomarker for ovarian cancer detection. See, e.g., Suh KS, Park SW, Castro A, Patel H, Blake P, Liang M, Goy A. Ovarian cancer biomarkers for molecular biosensors and translational medicine. Expert Rev. Mol. Diagnostics
  • CA-125 a useful tool for detecting ovarian cancer after the onset of symptoms. See, Id. Monitoring CA-125 blood serum levels is also useful for determining how ovarian cancer is responding to treatment (with the duration of disease-free survival correlating with the rate of fall of CA- 125) and for predicting a subject's prognosis following treatment. See, e.g., Santillan A, Garg R, Zahurak ML, Gardner GJ, Giuntoli RL, Armstrong DK, Bristow RE.
  • Prognosis relates to both the initial and post-treatment CA-125 values.
  • a preoperative value >65 U/mL suggests a poor prognosis.
  • Persistent elevations following cancer treatment agent therapy indicate a poor prognosis.
  • the half-life of CA-125 after cancer treatment agent therapy correlates with prognosis (subjects with CA-125 half-life ⁇ 20 days show improved survival).
  • Time-to-normalization rate of fall of CA-125) affects prognosis with more rapid normalization within 3 cycles of cancer treatment agent therapy correlating with improved survival. See, Mais DD, Leonard GR (2009). Quick Compendium Companion or Clinical Pathology (2nd ed.). Chicago: American Society for Clinical Pathology, p. 352.
  • CA-125 The potential role of CA-125 for the early detection of ovarian cancer is controversial and has not yet been adopted for widespread screening efforts in asymptomatic women.
  • the major issues with using the CA-125 biomarker are its lack of sensitivity, particularly for detecting early stages of ovarian cancer, and its lack of specificity, especially in
  • premenopausal women See, e.g., Nossov V, Amneus M, Su F, Lang J, Janco JM, Reddy ST, Farias-Eisner R.
  • the early detection of ovarian cancer from traditional methods to proteomics. Can we really do better than serum CA-125? Am. J. Obstet. Gynecol. 199(3):215- 223 (2008).
  • CA-125 testing often gives false positives for ovarian cancer and puts subjects through unnecessary further screening (sometimes including surgery) and anxiety.
  • these limitations mean that many women with early stage ovarian cancer may receive a false negative from CA-125 testing and not get further treatment for their condition.
  • CA-125 has limited specificity for ovarian cancer because elevated CA-125 levels can be found in individuals without ovarian cancer.
  • CA-125 is best known as a marker for ovarian cancer, it may also be elevated in other cancers, including endometrial, fallopian tube, lung, breast, and gastrointestinal cancers. See, e.g., Bast RC, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB. CA 125: the past and the future. Int. J. Biol. Markers
  • CA-125 may also be elevated in a number of relatively benign conditions, such as endometriosis, several diseases of the ovary, menstruation, and pregnancy. It also tends to be elevated in the presence of any inflammatory condition in the abdominal area, both cancerous and benign. Thus, CA-125 testing is not perfectly specific for ovarian cancer and often results in false positives. The specificity of CA-125 is particularly low in premenopausal women because many benign conditions that cause fluctuations in CA-125 levels, such as menstruation, pregnancy, and pelvic inflammatory disease (PID), are seen in this population. Elevations in CA-125 can also be seen in cirrhosis and diabetes mellitus.
  • CA-125 testing is also not perfectly sensitive for detecting ovarian cancer because not every subject with cancer will have elevated levels of CA-125 in their blood. For example, 79% of all ovarian cancers are positive for CA-125, whereas the remainder do not express this antigen at all. See, e.g., Rosen DG, Wang L, Atkinson TN, Yu Y, Lu KH, Diamandis EP, Hellstrom I, Mok SC, Liu J, Bast RC. Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol. Oncol. 99(2):267-277 (2005). Also, only about 50% of subjects with early stage ovarian cancer have elevated CA-125 levels. Since many subjects with early stage ovarian cancer do not have elevated levels of CA-125, this biomarker has poor sensitivity for ovarian cancer, especially before the onset of symptoms.
  • test is less reliable as values are often elevated due to a number of non-cancerous causes, and a value above 35 is not necessarily a cause for concern.
  • CA-125 has great utility to differentiate benign from malignant processes.
  • the positive predictive value is >95% for ovarian malignancy.
  • subjects who are not as carefully selected clinically the utility of this test decreases, thus highlighting the need for careful clinical scrutiny.
  • MUC16 has been shown to play a role in advancing tumorigenesis and tumor proliferation by several different mechanisms.
  • One mechanism by which MUC16 aids in the growth of tumors is by suppressing the response of Natural Killer Cells, thus protecting cancer cells from the immune response. See, e.g., Patankar MS, Jing Y, Morrison JC, Belisle JA, Lattanzio FA, Deng Y, Wong NK, Morris HR, Dell A, Clark GF. Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol. Oncol. 990 ⁇ :7O4-713 (2005). Further evidence of the role of MUC16 in allowing tumor cells to evade the immune system is the discovery that the heavily glycosylated tandem replete domain of MUC16 can bind galectin-1, an immunosuppressive protein.
  • MUC16 is also thought to participate in cell-to-cell interactions that allow for the metastasis of tumor cells. This is supported by evidence showing that MUC16 binds selectively to mesothelin, a glycoprotein normally expressed by the mesothelial cells of the peritoneum. MUC16 and mesothelin interactions are thought to provide the first step in tumor cell invasion of the peritoneum. See, e.g., Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A. Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J. Biol. Chem.
  • mesothelioma mesothelioma
  • ovarian cancer ovarian cancer
  • squamous cell carcinoma mesothelioma
  • MUC16 cytoplasmic tail of MUC16 enables tumor cells to grow and become motile and invasive. This appears to be due to the ability of the C-terminal domain of MUC16 to decrease the expression of E-cadherin and increase the expression of N-cadherin and vimentin, which are expression patterns consistent with epithelial - mesenchymal transition. See, e.g., Theriault C, Pinard M, Comamala M, Migneault M, Beaudin J, Matte I, Boivin M, Piche A, Rancourt C. MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecol. Oncol. 121(3):434-443 (2011).
  • MUC16 may also play a role in reducing the sensitivity of ovarian cancer tumor cells to drug therapy. Overexpression of MUC16 has been shown to protect cells from the effects of genotoxic drugs, such as cisplatin. See, e.g., Boivin M, Lane D, Piche A, Rancourt C. CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis. Gynecol. Oncol. 115(3):407-413 (2009).
  • the observations in the instant Karenitecin Phase III Trial regarding the ability of the subjects receiving Karenitecin: (i) to tolerate the full treatment cycle; (ii) to tolerate a greater number of chemotherapeutic cycles; and (iii) to have a reduction in cancer treating agent-related toxicities, may markedly improve the probability of advanced ovarian cancer being able to be treated as a chronic disease or even for a cure.
  • stage III/IV The existing recommended treatment strategy for subjects with advanced- stage ovarian cancer (stage III/IV) includes cytoreductive surgery ⁇ i.e., removal of all visible tumor) followed by platinum- and/or taxane-based cancer treating agent therapy - generally cisplatin or carboplatin with paclitaxel. See, e.g., Karlan BY, Markman MA, Eifel PJ.
  • the treatment strategy for subjects with recurrent ovarian cancer is based upon the initial cancer treating agent regimen used and on the initial response to treatment.
  • Patients who respond to a platinum-based cancer treating agent regimen and then experience a relapse after a disease-free interval of more than 6 months are considered platinum-sensitive (i.e., having a likelihood of achieving a secondary response, wherein said likelihood increases as the duration of disease-free interval increases); and are retreated with a platinum-based cancer treating agent regimen.
  • a single-agent carboplatin regimen is the currently preferred platinum compound for treatment of such platinum-sensitive recurrent disease. See, Id.
  • Oxaliplatin or paclitaxel in subjects with platinum pretreated advanced ovarian cancer a randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol. 2000;18(6): 1193-1202.
  • the use of a non-platinum regimen may extend the platinum-free interval with less risk of cumulative toxicity. See, e.g., Markman M, Bookman MA. Second-line treatment of ovarian cancer. The Oncologist 5:26-35 (2000).
  • the optimal therapeutic approach for the treatment of relapsed, advanced ovarian cancer would be based upon an understanding of the molecular genetics and biology of the disease; as well as the limitations of the initial therapy utilized. See, e.g., Ozols RF.
  • Therapeutic options include retreatment with platinum and/or paclitaxel, although it should be noted that subjects retreated with carboplatin and paclitaxel are at increased risk from cumulative hematologic toxicity (e.g., anemia, thrombocytopenia, neutropenia).
  • Other treatment options in the relapsed setting include initiation of a non-cross-resistant cancer treating agent or the use of investigational agents in the context of a clinical trial.
  • the outcome of second-line cancer treating agent therapy in relapsed ovarian cancer can be partially predicted by whether the disease is drug-sensitive (i.e., response duration more than six months) or drug-resistant (i.e., response duration less than six months). See, e.g., McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin. Oncol. 25:340-348 (1998). Patients with tumors classified as drug sensitive have demonstrated relatively high response rates (40-50%) to second-line platinum-based therapy. The time that elapses after the completion of the initial platinum-based therapy is defined as the platinum- free interval. In general, the longer the platinum-free interval, the higher the response rate to subsequent retreatment of the subject.
  • subjects who do not respond to a platinum- and/or taxane -based cancer treating agent regimen or who relapse within 6 months after completing a platinum- and/or taxane -based regimen are considered to be refractory or resistant to platinum and/or taxane cancer treating agents; and are generally not re-treated with these same regimens, as they have response rates to second-line platinum-based therapy as low as 10%>.
  • platinum- and/or taxane -based cancer treating agent regimen subjects who do not respond to a platinum- and/or taxane -based cancer treating agent regimen or who relapse within 6 months after completing a platinum- and/or taxane -based regimen are considered to be refractory or resistant to platinum and/or taxane cancer treating agents; and are generally not re-treated with these same regimens, as they have response rates to second-line platinum-based therapy as low as 10%>.
  • the aforementioned difference between drug-sensitive and drug-resistant tumors was initially described in relationship to platinum-based therapy, but is also
  • Extending the platinum-free interval in recurrent ovarian cancer after first relapse by using an alternative cancer treating agent regimen may help to increase the response to platinum analogue drugs that may be subsequently administered at the time of further disease progression.
  • the availability of newer non-cross-resistant cancer treating agents (which will be discussed infra) has expanded the treatment options for subjects with relapsed disease.
  • the camptothecin derivative, topotecan has demonstrated efficacy comparable to paclitaxel across all categories of platinum sensitivity and exhibited activity in subjects with ovarian cancer which has shown to be resistant to both platinum and paclitaxel.
  • Serum CA-125 level >35 U/ml Serum CA-125 level ⁇ 35 U/ml
  • Platinum sensitivity defined herein as the disease-free or treatment- free interval, has emerged as an important and significant predictor of response to second-line cancer treating agent therapy in a number of clinical studies conducted over the past two decades. See, e.g., Kavanagh H, Tresukosol D, Edwards C et al., Carboplatin reinduction after taxane in subjects with platinum-refractory epithelial ovarian cancer. J. Clin. Oncol. 13: 1584-1588 (1995). Patients who responded to first- line therapy and demonstrated a significant treatment-free interval also had a high probability of responding again to platinum-based treatment. See, e.g., Thigpen JT, Vance RB, Khansur T. Second-line chemotherapy for recurrent carcinoma of the ovary. Cancer 71: 1559-1564 (1993).
  • the first category is platinum-sensitive disease, which includes subjects who have relapsed more than six months after completing prior platinum therapy, usually in association with a clinical complete remission.
  • subjects who have been platinum-free (and disease-free) for more than two years have the greatest likelihood of response and are often retreated with a combination of platinum and paclitaxel. See, e.g., McGuire WP, Ozols RF. Chemotherapy of advanced ovarian cancer. Semin. Oncol. 25 :340-348 (1998).
  • Platinum-resistant disease includes subjects that have relapsed within six months of prior platinum therapy. As a group, the expected response rate to retreatment with platinum is less than 20%, although some subjects may remain platinum-sensitive. See, e.g., Markman M. Recurrence within 6 months of platinum therapy: an adequate definition of "platinum-refractory" ovarian cancer? Gynecol. Oncol. 69:91-92 (1998).
  • the third category is platinum-refractory disease, which can be defined as disease that progressed or was stable during prior platinum therapy.
  • the response rate for the subgroup of 26 subjects with a platinum-free interval of 12 months was 27% (7/26). Of clinical importance were three subjects who had progressed on initial platinum treatment before taxane therapy and who then achieved partial responses to carboplatin reinduction. Kavanagh and colleagues suggested that since all of the subjects who responded to carboplatin reinduction were taxane - sensitive: (a) taxane exposure may have eliminated the platinum-resistant clone and/or (b) the prolonged platinum-free interval may have resulted in loss of acquired platinum resistance. Therefore, they surmised that the likelihood of achieving a response in subjects with initially platinum-sensitive tumors increases when the interval from the last cycle of initial platinum- based treatment is longer than 12 months. That time interval may allow for the regrowth of platinum-sensitive cells or for resistant cells to lose their resistance to the cytotoxic drugs.
  • both cisplatin and carboplatin are associated with potential long-term hematologic and non-hematologic toxicities that may limit the amount and/or duration of therapy.
  • Recurrent ovarian cancer is generally incurable, and therapeutic strategies need to be integrated with maintenance of quality of life and associated endpoints.
  • the use of non-platinum-based therapies to extend the platinum-free interval and reduce the impact of cancer treating agent-related side effects and toxicities may maintain a higher quality of life and improve the likelihood of responding to subsequent retreatment with platinum with better tolerability.
  • Cancer treating agents that have been shown to have some activity in subjects with platinum- and/or paclitaxel-resistant ovarian cancer include, but are not limited to,
  • Topotecan oral etoposide, gemcitabine, liposomal doxorubicin, vinorelbine, and altretamine. See, e.g., Karlan BY, Markman MA, Eifel PJ. Ovarian cancer, peritoneal carcinoma, and fallopian tube carcinoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer.
  • Drugs that are currently approved by the United States Food and Drug Administration (FDA) for the treatment of recurrent ovarian cancer include: (i) Taxol (paclitaxel, Bristol-Myers Squibb Company); (ii) Hycamtin (Topotecan, GlaxoSmithKline); (iii) Doxil (doxorubicin HC1 liposomal, Janssen); and (iv) Gemzar (gemcitabine, Eli Lilly) administered in combination with carboplatin.
  • FDA United States Food and Drug Administration
  • Doxorubicin liposomal-formulation is an anthracycline antibiotic, closely related to the natural product daunomycin. Like all anthracyclines, it works by intercalating DNA.
  • the drug is administered intravenously, as the hydrochloride salt. It may also be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex.
  • Doxil is typically administered one a month at a dose of 50 mg/m of body surface area, at a rate of
  • doxorubicin administration is life -threatening heart damage and/or heart conditions ⁇ e.g., congestive heart failure, cardiac arrhythmias, and the like). See, e.g., Sneader, Walter (2005). Drug Discovery: A History. New York: Wiley, p. 467.
  • Gemcitabine is a nucleoside analog in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine.
  • the triphosphate analogue of gemcitabine replaces one of the nucleic acid building blocks, in this case cytidine, during DNA replication. This replacement process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" nucleoside, resulting in cellular apoptosis.
  • Another target of gemcitabine is the enzyme ribonucleotide reductase (RNR).
  • RNR ribonucleotide reductase
  • the camptothecin, Topotecan is a treatment option for subjects with advanced epithelial ovarian cancer. See, e.g., Herzog TJ. Update on the role of Topotecan in the treatment of recurrent ovarian cancer. The Oncologist. 7:3-10 (2002).
  • the principal toxicity of Topotecan is myelosuppression, which may limit its use in platinum-resistant subjects due to often incomplete bone marrow recovery following previous platinum treatment.
  • the silicon-containing HLCD was specifically developed to markedly improve key limitations of other camptothecins, which include: (i) safety; (ii) antitumor activity; (iii) potency; (iv) metabolism; (v) bioavailability; and (vi) sensitivity to multi-drug resistance proteins.
  • camptothecins which include: (i) safety; (ii) antitumor activity; (iii) potency; (iv) metabolism; (v) bioavailability; and (vi) sensitivity to multi-drug resistance proteins.
  • Karenitecin is at least 600-fold less water soluble than camptothecin.
  • Karenitecin has demonstrated clinical activity that appears to be superior to that of Topotecan.
  • the safety profile of Karenitecin suggests a reduced incidence of severe (NCI-CTCAE > grade 3) hematologic toxicity.
  • an improved hematologic toxicity profile may reduce the need for frequent monitoring of bone marrow function and treatment interventions ⁇ e.g., treatment delays, dose reductions, red blood cell [RBC] transfusions, growth factor support, and the like), thus improving subject safety and compliance, as well as the overall clinical benefit.
  • treatment interventions e.g., treatment delays, dose reductions, red blood cell [RBC] transfusions, growth factor support, and the like
  • results from three Phase I studies indicate that Karenitecin can be safely administered to subjects at the dose level of 1.0 mg/m /day i.v. over a one hour period of time for 5 consecutive days in a 3-week treatment cycle.
  • the principal and dose-limiting toxicity is non-cumulative, reversible myelosuppression. Any gastrointestinal toxicity is generally ⁇ grade 2 and is not dose-limiting.
  • Phase III clinical trial was critical for the inventions disclosed in the instant patent application in order to allow the evaluation of Karenitecin in this specific and rigorously selected subject population with a larger number of subjects in which detailed measurements of PFS, total number of subject treatment cycles, safety related events, and other important clinical observations could be made in a larger subject population.
  • PFS was radiographically determined by an Independent Radiological Committee (IRC).
  • IRC Independent Radiological Committee
  • highly specific or advanced methodologies were used to, e.g., initially select, diagnosis, and/or define the subject population of the instant Phase III clinical trial.
  • the subject population selected for inclusion in the instant Phase III clinical trial were all refractory and/or resistant to a platinum- and/or taxane -based cancer treating agent regimen.
  • the subject population selected for inclusion in the instant Phase III clinical trial were all refractory and/or resistant to a platinum- and/or taxane -based cancer treating agent regimen.
  • the subject population selected for inclusion in the instant Phase III clinical trial were all refractory and/or resistant
  • CPT was isolated from Camptotheca acuminata, a tree native to China, its chemical structure was characterized, and evidence of potent antitumor activity was documented. See, e.g., Wall, M.E., et al., Plant antitumor agents.
  • camptothecin a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J. Am. Chem. Soc. 88:3888-3890 (1966).
  • the naturally-occurring CPTs possessed antitumor activity, product formulation and delivery were problematic due to poor water solubility.
  • the water-soluble sodium salt form (or carboxylate form) of CPT was used in early clinical trials.
  • the structure of this originally isolated camptothecin (CPT) is shown below:
  • Topoisomerase I the target enzyme of the camptothecins, is a 100 kDa protein composed of 765 amino acids.
  • the enzymatic activity of topoisomerase I is found in a 67.7 kDa region located at the carboxyl -terminal end of the protein.
  • the topoisomerase I gene is located on human chromosome 20, and it consists of 21 exons extending over 85 kilobases of DNA. Expression of topoisomerase I is found in nearly all mammalian cells at a high copy number, estimated at approximately 10 6 per cell. See, e.g., Kunze, N., et al, The structure of the human type I DNA topoisomerase gene. J. Biol. Chem.
  • Topoisomerase I acts to relax supercoiled double-stranded DNA, a function it partially shares with the related enzyme topoisomerase II. Unwinding of the DNA helix is essential for normal DNA function such as DNA replication or RNA transcription. This unwinding generates torsional strains in the DNA resulting form supercoiling of the helix above and below the region of ongoing nucleic acid synthesis. Topoisomerase I relaxes both positively- and negatively-supercoiled DNA and allows these functions to proceed in an orderly fashion. Although its exact role has not been fully elucidated, the involvement of topoisomerase I in RNA transcription has been postulated.
  • topoisomerase I has been localized by immunohistochemical methods to regions of the nucleus that are active in RNA transcription, such as the nucleolus. See, e.g., Muller, M., et ah, Eukaryotic type I topoisomerase is enriched in the nucleolus and catalytically active on ribosomal DNA. EMBO J. 4: 1237 (1988). Although little is known about the regulation of topoisomerase I activity, phosphorylation by protein kinase C appears to activate the enzyme.
  • topoisomerase I is constitutively expressed at relatively constant levels throughout the cell cycle, even in cells that are actively dividing.
  • inhibitors of topoisomerase I such as the camptothecins, may potentially be active in tumors that have low growth fractions and are resistant to other anticancer agents.
  • higher levels of topoisomerase I protein and mRNA were found in malignant colon and prostate tumors relative to their normal counterparts. See, e.g., Hussain, I, et ah, Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors. Cancer Res. 54:539 (1994). Consequently, the camptothecins may be selectively toxic to tumor cells compared with normal tissues.
  • Topoisomerase I preferentially binds to supercoiled double-stranded DNA and cleaves the phosphodiester bond, resulting in a single-strand nick.
  • the topoisomerase I enzyme is temporarily bound by a covalent bond between a tyrosine residue at position 723 and the 3'- terminus of the single-strand break in the DNA.
  • This normally short-lived intermediate has been called the cleavable complex, and once it has been formed, free rotation of the DNA molecule can occur about the remaining intact phosphodiester bond, allowing for the relaxation of the torsional strain in the DNA.
  • camptothecins In the presence of camptothecins, the topoisomerase I enzymatic reaction is altered, resulting in a drug-induced stabilization of the cleavable complex. See, e.g., Potmesil, M., Camptothecins from bench research to hospital ward. Cancer Res. 54: 1431 (1994).
  • Camptothecins interact non-covalently with the DNA-bound topoisomerase I and inhibit the relegation step of the reaction. Consequently, there is accumulation of stabilized cleavable complexes and a persistence of single-stranded DNA breaks.
  • this DNA damage alone is not toxic to the cell, because the lesions are highly reversible and can be repaired rapidly once the drug is removed. Instead, ongoing DNA synthesis is required in order to convert these stabilized cleavable complexes into more lethal DNA damage. See, e.g., D'Arpa, P., et al., Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 50:6919 (1990).
  • camptothecins should be highly S-phase cell-cycle-specific in their action. This finding has been confirmed in most, but not all experimental studies. This point has important implications for the design of clinical therapeutic regimens, because highly S -phase-specific cytotoxic agents require prolonged exposures to drug concentrations above a minimum threshold in order to maximize the fractional cell kill.
  • camptothecins can clearly produce irreversible DNA damage in the presence of ongoing DNA synthesis, the events responsible for cell death once these lesions occur have been elucidated fully.
  • the molecular mechanisms responsible for regulation this block in the cell cycle have been examined. Camptothecin- induced DNA damage correlates with altered activity of the p34 cdc2 /cyclm B complex, which has been tightly linked to regulation of the G 2 to M-phase transition in the cell cycle.
  • Camptothecins also can damage DNA at the chromosomal level.
  • Dose-dependent increases in sister chromatid exchange (SCE) and chromosomal aberrations were detected in the peripheral blood lymphocytes obtained from subjects following irinotecan treatment. See, e.g., Kojima, A., et al, Cytogenetic effects of CPT-11 and its active metabolite, SN-38, on human lymphocytes. Jpn. J. Clin. Oncol 23: 116 (1993). The chromosomal damage was manifested mainly by chromatid gaps and breaks.
  • camptothecin therapy Although little is known concerning the possible long-term side effects of camptothecin therapy, other DNA-damaging agents, such as alkylating agents, have been associated with mutagenicity. Additional study will be required to determine whether these risks are also relevant to the camptothecins.
  • topoisomerase I The presence of topoisomerase I is essential for the generation of camptothecin- induced cytotoxicity. Mutant yeast cells that lack functional topoisomerase I are completely resistant to the camptothecins. However, when topoisomerase I is transfected into these mutants, drug sensitivity is restored. See, e.g., Nitiss, J. and Wang, J.C., DNA topoisomerase targeting antitumor drugs can be studied in yeast. Proc. Natl Acad. Sci. U.S.A. 85 :7501 (1988). These experiments illustrate how camptothecin' s mechanism of action differs from the more traditional pharmacologic inhibition of an essential enzyme. In order to generate drug toxicity, complete inhibition of topoisomerase I is not necessary or even required. Instead, the camptothecins generate drug toxicity by converting a normally functioning constitutive protein, topoisomerase I, into a cellular poison.
  • Topoisomerase I cleavage is not a random event and the single-strand nicks appear with increase frequency at specific sequence sites in the DNA. See, e.g., Jaxel, C, et ah, Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. J. Biol. Chem. 266:20418 (1991). Interestingly, camptothecin does not stabilize all topoisomerase I cleavable complexes equally. Instead, enhanced stabilization of cleavage sites by camptothecin occurs when a guanine residue is immediately 3 ' to the phosphodiester bond normally cleaved by the enzyme.
  • topoisomerase I has no specific base preference at this location, suggesting that only a subset of the total topoisomerase I cleavage sites is stabilized by camptothecin.
  • camptothecin stacking model in which the drug specifically interacts with guanine residues at the topoisomerase I-DNA cleavage site.
  • camptothecin derivatives may stabilize different topoisomerase I cleavage sites. See, e.g., Tanizawa, A., et al., Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J. Natl. Cancer Inst. 86(11):836 (1994). An in-depth understanding of these site-specific interactions will be greatly facilitated by crystallographic characterization of the molecular structure of the camptothecin- stabilized cleavable complex.
  • camptothecin resistance has been characterized in several different cell lines.
  • Single-base mutations in the topoisomerase I enzyme can decrease its interaction with the camptothecins, resulting in drug resistance.
  • Recently, several different amino acid substitutions have been characterized in human topoisomerase I that confer a relative resistance to the camptothecins. These substitutions span a large portion of the protein, and they include changing a glycine 363 to cysteine, threonine 729 to alanine, and phenylalanine 301 to serine or aspartic acid 533 or 583 to glycine. See, e.g., The Camptothecins.
  • topoisomerase I mutants with relative camptothecin resistance.
  • Insensitivity to the camptothecins also can result from decreased expression of topoisomerase I.
  • a resistant subline of cells containing less than 4% of the topoisomerase I activity compared with wild-type parental cells was 1000-fold less sensitive to camptothecin.
  • the decreased expression of topoisomerase I in this cell line was compensated for by a corresponding increase in topoisomerase II expression.
  • topoisomerase I Postulated mechanisms responsible for the decreased expression of topoisomerase I include chromosomal deletions or by permethylation of the topoisomerase I gene. See, e.g., Tan, K.B., et ah, Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors. J. Natl. Cancer Inst. 81_: 1732 (1994).
  • MDR P-glycoprotein-associated multidrug resistance
  • Camptothecin overcomes MDR 1 -mediated resistance in human KB carcinoma cell lines. Cancer Res. 51:6039 (1991). No increase in resistance was observed for camptothecin or 10,11-methylenedioxycamptothecin. While other investigators have confirmed these observations, this degree of MDR-associated resistance is much less than the 200-fold change in sensitivity typically described for classic MDR substrates, such as doxorubicin or etoposide, in the same experiments. See, e.g., Mattern, M.R., et ah, In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells. Oncology Res. 5:467 (1993). The relevance of these observations to the clinical setting requires further study.
  • camptothecin resistance Another potential mechanism for camptothecin resistance is decreased intracellular drug accumulation, which was observed in vitro.
  • the biochemical processes responsible for these decreased intracellular drug levels have not been identified, and unfortunately, little is currently known about the mechanisms of camptothecin influx and efflux from cells.
  • resistance to a camptothecin prodrug, such as irinotecan may result from decreased intracellular production of the active metabolite SN-38 by the irinotecan converting-enzyme carboxylesterase.
  • a preliminary association has been reported between the measured converting-enzyme activity in different tumor cell lines and their relative sensitivity to irinotecan.
  • topoisomerase I are important, other factors are also essential, including the degree of drug sensitivity of the topoisomerase I enzyme, the number of cleavable complexes stabilized, and the extent of ongoing DNA synthesis. Equally important, but even less understood, events that contribute to camptothecin cytotoxicity include DNA damage repair, the triggering of apoptosis, and alteration of the integrity of cell cycle control by, for example, G 2 check-point arrest. A detailed understanding of the relationship between each of these processes and camptothecin-induced cell death remains an important research goal.
  • CPTs camptothecins
  • CPT lactone species substantially higher in mice than in humans for CPT-11 and SN-38 (the active metabolite of CPT- 11), 9-amino-camptothecin (9-NH 2 -CPT, or 9-AC), 9-nitro-camptothecin (9-N0 2 -CPT), and CPT.
  • concentration of the lactone species of the CPTs in human plasma is thought to have a substantial effect in reducing the antitumor activity of CPTs containing the 20(5) lactone firing moiety.
  • the clinical utility of commercially available water-soluble CPTs may be limited by the following: reduced tissue diffusion and uptake, unfavorable variability in drug activation and/or metabolism, common clinical toxicities that can be dose-limiting, and susceptibility to tumor-mediated drug resistance mechanisms.
  • HLCDs Highly lipophilic camptothecin derivatives
  • silicon-based moieties are effective anti-cancer drugs.
  • One of the most noted of the silicon- containing HLCDs is Karenitecin (also known as BNP1350; cositecan; IUPAC
  • Karenitecin and various analogs thereof, represent a novel class of cancer treating agents that have exhibited potent antineoplastic activity against common types of cancer including but not limited to cancers of the lung, breast, prostate, pancreas, head and neck, ovary, colon, as well as melanoma. While Karenitecin possesses Topoisomerase I inhibitory activity similar to that of other camptothecin derivatives, it also possess novel structural modifications that are rationally designed for superior bioavailability and tissue penetration, while concomitantly avoiding untoward metabolism and drug resistance mechanisms which are common in human and other mammalian cancers.
  • camptothecin is a HLCD characterized by substantial lactone stability and long plasma half-life.
  • in vitro studies conducted on a panel of over twenty (20) human cancer cell lines indicate that Karenitecin is a significantly more potent antitumor agent than either Topotecan or SN-38, the active metabolite of Irinotecan.
  • Equilibrium dialysis studies with human plasma demonstrated that Karenitecin is 98 to 99% protein-bound.
  • the free drug concentration in blood plasma is generally considered to be the pharmacologically active form in clinical pharmacology.
  • Karenitecin has significant utility as a highly efficacious cancer treating agent, and is significantly less toxic than previously disclosed camptothecin derivatives.
  • Karenitecin also does not undergo A-ring or B-ring glucuronidation (and implicitly deglucuronidation).
  • the lack of glucuronidation decreases deleterious physiological side- effects (e.g., diarrhea, leukopenia) and may also mitigate substantial intersubject variability in drug levels of the free metabolite and its glucuronide conjugate.
  • Karenitecin is not a prodrug, thus it requires no metabolic activation.
  • Karenitecin (i) possesses potent antitumor activity (i.e., in nanomolar or sub-nanomolar concentrations) for inhibiting the growth of human and animal tumor cells in vitro; (ii) is a potent inhibitor of Topoisomerase I; (iii) lacks susceptibility to MDR/MRP drug resistance; (iv) requires no metabolic drug activation; (v) lacks
  • glucuronidation of the A-ring or B-ring reduces drug-binding affinity to plasma proteins; (vii) maintains lactone stability; (viii) maintains drug potency; and (ix) possesses a low molecular weight (e.g., MW ⁇ 600).
  • Karenitecin is a novel, HLCD and is distinguished from other camptothecins on the basis of its highly novel chemical structure, possessing a tri -methyl silicon moiety.
  • some of the novel characteristics displayed by Karenitecin include, but are not limited to: (i) possesses potent antitumor activity (i.e., in nanomolar or sub-nanomolar concentrations) for inhibiting the growth of human and animal tumor cells in vitro; (ii) is a potent inhibitor of Topoisomerase I; (iii) lacks susceptibility to MDR/MRP drug resistance; (iv) requires no metabolic drug activation; (v) lacks glucuronidation of the A-ring or B-ring (which reduces inter-subject variability and gastrointestinal toxicity); (vi) reduces drug- binding affinity to plasma proteins; (vii) maintains lactone stability; (viii) maintains drug potency; and (ix) possesses a low molecular weight (e.g., MW ⁇ 600).
  • Karenitecin has a longer half-life in plasma, when compared with reported half-lives of various other commercially-available camptothecins.
  • Karenitecin also appears to be insensitive to all commonly-known tumor-mediated drug resistance mechanisms, including Breast Cancer Resistance Protein (BCRP), which is recognized to be a tumor-mediated drug resistance factor in human cancer for camptothecins. See, e.g., Maliedorfd, M., et al, Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to
  • Karenitecin has demonstrated significant anti-tumor activity in vitro and in vivo against various human xenograft tumor models for various tumor types including, but not limited to, human central nervous system (CNS), colon, melanoma, lung, breast, ovarian carcinoma, and glioblastoma multiform. See, e.g., Van Hattum, A.H., et al., Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of efficacy and possible mechanisms of resistance. Int. J. Cancer.
  • BNP1350 a novel, highly lipophilic, lactone stable camptothecin [abstract]. AACR Abstract 1360 (2000).
  • the relative antitumor activity of Karenitecin in preclinical models is similar or superior to the antitumor activity observed with other camptothecins, and Karenitecin has demonstrated a high degree ⁇ e.g., approximately 85%) of lactone stability in humans.
  • the Maximum Tolerated Dose (MTD) of orally administered Karenitecin was 0.075 mg/kg; approximately 2-times that of intravenous (i.v.) Karenitecin.
  • MTD Tolerated Dose
  • a toxicology study of various single daily doses of Karenitecin administered orally and intravenously for five consecutive days showed good tolerability of oral doses.
  • Toxicities were reversible and included: anorexia (seen in i.v. groups, but not oral groups); weight loss (high in i.v.
  • Gastrointestinal toxicities were dose-dependent, and were more severe in the higher drug treatment groups. Oral gastrointestinal toxicities were delayed and mild compared with i.v.-associated toxicities. Other clinical observations included: infusional toxicities, excitement, hyperpnea, facial and pinnae edema, pruritis, forced bowel movements, vomiting, increased tearing, and ptyalism.
  • DLTs dose-limiting toxicities
  • Intravenous administration of Karenitecin has been evaluated in three Phase I clinical studies in subjects with the following cancer types: (i) advanced solid tumors (adult subjects) (see, e.g., Schilsky, R.L., Hausheer, F.H., et al, Phase I trial of karenitecin administered intravenously daily for five consecutive days in subjects with advanced solid tumors using accelerated dose titration [abstract]. ASCO Abstract 758 (2000)); (ii) refractory or recurrent solid tumors (pediatric subjects); and (iii) recurrent malignant glioma (adult subjects).
  • Intravenous administration of Karenitecin has also been evaluated in four Phase 2 clinical studies in adult subjects with the following cancer types: (i) primary malignant glioma; (ii) third-line treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma; (iii) malignant melanoma (see, e.g., Hausheer, F.H., et al., Phase II trial of Karenitecin (BNP1350) in malignant melanoma: clinical and translational study [abstract].
  • a Phase I clinical trial (the "Oral Karenitecin Phase I Trial") was performed to determine the maximum tolerated dose (MTD) of oral Karenitecin in subjects with solid tumors given in a dose-escalated manner (starting at 0.5 mg/m ) and administered 3-times per week (MWF or TTS) for 3 consecutive weeks followed by a one -week treatment rest.
  • MTD maximum tolerated dose
  • MTF 3-times per week
  • Stage I subjects received Karenitecin as a single oral dose 3 times per week for 3 consecutive weeks followed by a one -week treatment rest.
  • Stage 1 some of subjects underwent pharmacokinetic sampling, and first received a single i.v. dose of Karenitecin (at the appropriate dosage level) followed by oral Karenitecin 4 to 7 days following the i.v. dose on a MWF or TTS schedule. Patients then received oral Karenitecin for all subsequent treatments. Patients who did not undergo pharmacokinetic sampling, only received oral Karenitecin on a MWF or TTS schedule.
  • Table II illustrates the dose escalations (or de-escalations) utilized in Stage 1 using an accelerated dose titration study design.
  • 0.5 mg/m /day 0.5 mg/m /day i.v. doses should be rounded to the nearest 0.1 mg ( ⁇ 0.04 round down, > 0.05 round up).
  • Oral doses should be rounded to the nearest 0.25 mg daily dose.
  • DLT dose-limiting toxicity
  • NCI CTCAE grade 2 toxicity
  • a patient with advanced ovarian cancer participating in the Phase I trial of orally administered Karenitecin remained on the trial for approximately 16 months with no evidence of progressive disease.
  • a patient with neuroendocrine cancer participating in the oral Karenitecin trial remained on the trial for approximately 23 months with no evidence of progressive disease.
  • a patient with breast cancer participating in the oral Karenitecin trial remained on the trial for approximately 19.5 months with no evidence of progressive disease.
  • a patient with non-small cell lung cancer participating in the oral Karenitecin trial remained on the trial for approximately 36 months with no evidence of progressive disease.
  • a patient with pancreatic cancer participating in the oral Karenitecin trial remained on the trial for approximately 7 months with no evidence of progressive disease.
  • a patient with melanoma participating in the oral Karenitecin trial remained on the trial for approximately 15 months with no evidence of progressive disease.
  • a patient with peritoneal papillary adenocarcinoma cancer participating in the oral Karenitecin trial remained on the trial for approximately 8 months with no evidence of progressive disease.
  • a patient with leiomyosarcoma participating in the oral Karenitecin trial remained on the trial for approximately 7 months with no evidence of progressive disease.
  • a patient with refractory small cell cancer participating in the oral Karenitecin trial remained on the trial for approximately 6 months with no evidence of progressive disease.
  • a patient with colorectal cancer participating in the oral Karenitecin trial remained on the trial for approximately 8 months with no evidence of progressive disease.
  • a patient with prostate cancer participating in the oral Karenitecin trial remained on the trial for approximately 7 months with no evidence of progressive disease.
  • a patient with sarcoma participating in the oral Karenitecin trial remained on the trial for approximately 9 months with no evidence of progressive disease.
  • a patient with carcinoma of the parotid gland participating in the oral Karenitecin trial remained on the trial for approximately 12 months with no evidence of progressive disease.
  • the natural progression of ovarian cancer is typically characterized by the subsequent development of broad cross-resistance to various cancer treating agents.
  • This resistance may develop from changes in drug-host metabolism, from the expansion of tumor cells to sites that are poorly responsive to cancer treating agents, from changes in expression levels of certain genes, and/or from biochemical changes at the cellular or subcellular level.
  • novel non-cross-resistant cancer treating agents such as Karenitecin, allows clinicians the opportunity to extend the platinum-free interval at the time of first relapse and increase the likelihood of response to platinum re-induction at the second relapse, and even overcome or delay acquired platinum resistance in some subjects.
  • camptothecin derivative such as Karenitecin includes its novel mechanism of action, its comparable efficacy compared with paclitaxel in subjects with recurrent drug-sensitive disease, and its non-cumulative, well-characterized toxicity profile based upon clinical trial experience, including a recent Phase III clinical trial.
  • camptothecins such as Karenitecin have a novel mechanism of action distinct from platinum compounds, taxanes, alkylating agents, and various other cancer treating agents previously used in the treatment of ovarian cancer.
  • Topoisomerase I is an enzyme that is critical for cell growth and proliferation. It catalyzes the cutting and ligating of a single DNA strand and is required for DNA replication, DNA repair, and gene expression.
  • Karenitecin exerts its cytotoxic effect by disrupting this DNA breakage/religation process that occurs during replication, thus resulting in tumor cell death.
  • the general mechanisms of antineoplastic drug resistance include decreased drug
  • Topoisomerases may be the final common cytotoxic pathway for several different classes of cancer treating agents (including platinum compounds). Drugs that act through topoisomerases prevent the re-ligation of DNA as a consequence of cleavable complex formation. Through this mechanism, Karenitecin can potentially interfere with repair from cisplatin-induced DNA damage (a major mechanism of cisplatin resistance).
  • camptothecin derivative such as Karenitecin
  • platinum Upon relapse of disease, second-line therapy with a camptothecin derivative, such as Karenitecin, rather than the re-administration of platinum, could theoretically maximize the effectiveness of both agents.
  • responses to the camptothecin derivative, topotecan are highest when used in first-relapse, drug-sensitive disease; as well as responses to platinum therapy are highest when the platinum-free interval is extended.
  • second-line therapy with platinum prior to topotecan can actually promote the development of drug resistance and reduce the subsequent likelihood of response to topotecan.
  • a number of safety-related factors must be considered when selecting a second-line regimen in relapsed ovarian cancer, including quality of life, the type and degree of prior platinum- and taxane-induced toxicities, and subject preferences about their treatment.
  • Treatment with platinum compounds in relapsed ovarian cancer may be compromised by cumulative toxicities, especially in heavily pretreated subjects, older subjects, and subjects with preexisting nephrotoxicity.
  • Administration of cancer treating agents with substantial toxicity to subjects with multiple prior therapies may require dose delays or dose reductions because of, e.g., diminished bone marrow reserves (from carboplatin) or renal impairment (from cisplatin).
  • Earlier utilization of Karenitecin may reduce the likelihood of dose-limiting hematologic toxicities.
  • the primary goal of therapy in relapsed ovarian cancer is to extend survival by maximizing all available therapies while minimizing deleterious side effects and preserving quality of life. See, e.g., NIH Consensus Development Panel on Ovarian Cancer. Ovarian cancer: screening, treatment, and follow-up. JAMA 273:491-497 (1995).
  • the choice of therapy for relapsed ovarian cancer is generally based upon the timing and characteristics of the relapse, as well as the type and extent of the prior treatment.
  • Tavocept is a sulfur-containing, amino acid-specific, small molecule that possesses the ability to function as a multi-target modifier and/or modulator of the function of multiple target molecules of therapeutic interest.
  • Tavocept mediates the non-enzymatic xenobiotic modification of sulfur-containing amino acid residues (e.g., cysteine) on proteins.
  • sulfur-containing amino acid residues e.g., cysteine
  • Tavocept is autocatalytic and requires no protein cofactor to cause the xenobiotic modification of cysteine, but appears to be specific for cysteine residues located within a particular structural context (i.e., not all cysteines in a protein are so modified).
  • Tavocept-mediated, xenobiotic modification represents a novel mechanism of action for a cancer treating agent and can be compared, to a degree, with post-translational modifications of cysteine residues in proteins (see, Table 3, below).
  • some of the important elements of Tavocept's effectiveness as a compound in the treatment of cancer are its selectivity for normal cells versus cancer cells and its absence of interference with the anti-cancer activity of cancer treating agents.
  • In vitro studies demonstrated that Tavocept does not interfere with paclitaxel induced apoptosis, as assessed by PARP cleavage, Bcl-2 phosphorylation, and DNA laddering in human breast, ovarian and lymphoma cancer cell lines. Additionally, Tavocept was shown not to interfere with paclitaxel- and platinum-induced cytotoxicity in human cancer cell lines.
  • Tavocept The believed mechanisms underlying the absence of interference with anti-cancer activity by Tavocept are multifactorial and, as previously discussed, may involve its selectivity for normal cells versus cancer cells, inherent chemical properties that have minimal impact in normal cells on critical plasma and cellular thiol-disulfide balances, and its interactions with cellular oxidoreductases, which are key in the cellular oxidative/reduction (redox) maintenance systems.
  • Tavocept may elicit the restoration of apoptotic sensitivity in tumor cells through, e.g., thioredoxin- and glutaredoxin-mediated mechanisms and this may be an important element of its effectiveness as a cancer treating agent.
  • Table 3 Tavocept Cysteine-Specific Protein Modifications
  • the percent of cell survival was determined using the SRB assay relative to survival seen in cells that were not treated with any test article.
  • the JHOM2B and OMC3 cell lines were purchased from Riken Cell Bank (Japan).
  • the COV644 cell line was purchased from SigmaAldrich.
  • Cells were maintained as monolayered cultures in T-75 flasks and then seeded to microtiter plate wells for experiments. Population doubling-times for these three cell lines were long (i.e., exceeding 40 hours, and for some of the cell lines approaching 96 hours); therefore, the Applicants conducted initial pilot experiments and determined optimal seeding density to obtain A 57 o values in untreated controls that would fall within the linear range of the SRB assay after seven (7) total days of cell growth.
  • JHOM2B cells were cultured in DMEM:F12 (1 : 1) + 0.1 mM non-essential amino acids (NEAA) + 10% FBS and were seeded at 6,000 cells per well.
  • OMC3 cells were cultured in HamF12 + 10% FBS and were seeded at 8,000 cells per well.
  • COV644 cells were cultured in DMEM + 2 mM glutamine + 10% FBS and were seeded at 6,000 cells per well.
  • the cells were manipulated in a Microzone laminar flow hood traditionally used for maintaining aseptic environments around automated instrumentation such as microplate robots, and the like.
  • Cells were grown and maintained at 37°C in a humidified atmosphere containing 5% C0 2 in a water-jacketed cell culture incubator (Forma Scientific). Cells were counted using a ViCell counter (Beckman-Coulter). An automated plate washer/stacker (ELx405/BioStak from BioTek Instruments) and a microplate reader (SpectraMax Plus from Molecular Devices) were used for conducting the SRB assay and determining A 57 o values for wells in the plates and the percentage of control values. Prior to SRB assays, cell viability was monitored by evaluation of microtiter plate wells. Dead cells detach and float while living cells remain attached to the bottom of the cell well.
  • BNP1350 (lot K -C192-135) and BNP7787 (lot 205001) were synthesized at BioNumerik Pharmaceuticals, Inc. (San Antonio, TX). BNP1350, SN38, and Topotecan were prepared as 2.5, 2.5, and 25 mM stocks in DMSO (ATCC, cell culture grade).
  • SRB sulforhodamine B cytotoxicity assay was used to assess cell survival. Briefly, after the medium was decanted from individual plate wells, trichloroacetic acid (100 ⁇ of 10.0 percent solution) was added to each well, and the plates were incubated at 4°C for 1 hour. The plates were washed five times with water using an automated microplate washer (Model ELx405, Bio-Tek Instruments), SRB solution (100 ⁇ , of 0.4% SRB dissolved inl .O percent acetic acid) was added, and plates remained at room temperature for 15 minutes.
  • SRB solution 100 ⁇ , of 0.4% SRB dissolved inl .O percent acetic acid
  • IC 50 values determined from dose-response curves are summarized in the tables below.
  • Tables 4a and 4b illustrate IC 50 values determined from does-response results in tabular summaries for JHOM2B data.
  • Figure 2 illustrates a summary of experiments evaluating effect of BNP7787 on BNP1350-induced cytotoxicity for JHOM2B data.
  • Tables 5 a and 5b illustrate IC50 values determined from dose-response results in tabular
  • Figure 3 illustrates a summary of experiments evaluating effect of BNP7787 on BNP1350-induced cytotoxicity for OMC3 data.
  • Tables 6a and 6b illustrate IC 50 values determined from does-response results in a tabular summaries for COV644 data.
  • Figure 4 illustrates a summary of experiments evaluating effect of BNP7787 on BNP1350-induced cytotoxicity for COV644 data.
  • IC50 values exceeded the solubility in medium for each compound - the limit of solubility in cell culture medium for the compounds were as follows: 2 micromolar for
  • BNP1350 and SN38 were treated for periods of 2.5 hours or 6 hours and, in each case, the IC50 values were not reached. Longer treatments were not performed.
  • BNP1350 Karenitecin
  • BNP1350 IC50 values were: JHOM2B 69.5 nM; OMC3 49.5 nM; and COV644 > 2 ⁇ .
  • Topotecan IC 50 values were: JHOM2B 5.17 ⁇ ; OMC3 3.94 ⁇ ; and COV644 > 20 ⁇ .
  • the Karenitecin Phase III Trial was a multi-center, multi-national, randomized, open- label, active-controlled, Phase III clinical study to evaluate the safety and efficacy of Karenitecin compared with Topotecan; wherein the drugs were administered to each trial subject as a single, daily intravenous dose of either Karenitecin or Topotecan - [Karenitecin 1.0 mg/m /day x 5 (first 5 consecutive days per cycle) in a 60 minute i.v. infusion or Topotecan 1.5 mg/m /day x 5 (first 5 days consecutive days per cycle) in a 30 minute i.v.
  • PFS Progression Free Survival
  • cancer treating agents are approved for use in subjects who have failed initial treatment for advanced ovarian cancer. Most, if not all approved agents for the treatment of subjects with advanced ovarian cancer are associated with significant toxicity, and therefore new agents need to be developed to assist in the achievement of the treatment goals.
  • Topotecan has been approved by the FDA for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy agent therapy. Topotecan has shown a trend to comparable or superior efficacy compared with both paclitaxel and Doxil in subjects with platinum-resistant or refractory ovarian cancer. See, e.g., Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus Topotecan. J. Clin.
  • Topotecan The hallmark toxicity of Topotecan is myelosuppression, which may also compound bone marrow toxicity from prior platinum therapy, thus necessitating very careful monitoring of hemoglobin (Hgb) levels, platelet counts, and neutrophil counts; as well as treatment interventions that include treatment delays, dose reductions, growth factor support, and RBC transfusions.
  • Hgb hemoglobin
  • the primary endpoint was Progression Free Survival (PFS); defined as the time period from the date of randomization to the date of first radiographically documented progressive disease (PD) or date of death due to any cause, taking the event date that occurs first.
  • PFS Progression Free Survival
  • PD radiographically documented progressive disease
  • RECIST radiographically objective disease
  • OS Overall Survival
  • NCI- CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • neutropenia including febrile neutropenia
  • neutropenia defined as the proportion of subjects who experience > grade 3 neutropenia based on NCI-CTCAE criteria at any time post-baseline after receiving study treatment.
  • Period I Session and Randomization: Patient eligibility was determined by compliance with protocol-specified inclusion and exclusion criteria. Patients who signed the informed consent, and successfully complete the screening process, including documentation of disease status by radiographic measures, were randomized to receive study treatment.
  • Period II Activity Treatment: During this period, subjects received either
  • Period III End of Treatment: Within ⁇ 3 days of date of treatment discontinuation, end-of treatment procedures were conducted during Period III. Tumor measurements and response assessments need to be completed during Period III if the regularly-scheduled tumor measurements/response assessments fall into the Period III time interval.
  • Period IV (Follow-Up for Progression and Survival): All subjects were followed for progression and survival. All subjects were assessed for best overall response at the time they reach PD or start any alternative therapy.
  • PFS median progression-free survival
  • HR Hazard Ratio
  • Median PFS was approximately 24.3 weeks for the Karenitecin arm compared to 17.8 weeks for the Topotecan arm.
  • the PFS for Karenitecin and Topotecan was determined using an Independent Radiologic Committee (IRC).
  • PFS progression- free survival
  • an overall survival (OS) of 35 months was observed in the third quartile of the Karenitecin arm for the Mucinous adenocarcinoma ovarian cancer subtype as compared to an OS of 19.4 months for the third quartile of the Topotecan arm for this subtype.
  • An improvement in the overall survival hazard ratio in favor of Karenitecin (as compared with Topotecan) was also observed in the "Histopathology class:
  • Mucinous adenocarcinoma subtype of trial subjects, resulting in an observed hazard ratio of 0.841, P-value 0.7321.
  • Median PFS was approximately 26.9 weeks for the Karenitecin arm for this subpopulation of patients compared to 18.7 weeks for the Topotecan arm for this subpopulation.
  • the PFS benefit for Karenitecin in comparison to Topotecan was determined using an
  • the PFS benefit for Karenitecin in comparison to Topotecan was determined using an Independent Radiologic Committee (IRC).
  • IRC Independent Radiologic Committee
  • An improvement in the overall survival hazard ratio in favor of Karenitecin (as compared with Topotecan) was also observed in the "Histological Stage: Gl-well differentiated" subtype of trial subjects, resulting in an observed hazard ratio of 0.9612, P-value 0.974.
  • Undifferentiated carcinoma subtype of trial subjects, resulting in an observed hazard ratio of 0.6426, P-value 0.701.
  • the number of grade 3 or 4 anemia events was reduced by 27.3% in the Karenitecin arm of the Karenitecin Phase III Trial in comparison to the Topotecan arm of the Karenitecin Phase III Trial.
  • the number of grade 3 or 4 thrombocytopenia events was reduced by 37.4% in the Karenitecin arm of the Karenitecin Phase III Trial in comparison to the Topotecan arm of the Karenitecin Phase III Trial.
  • the mucinous adenocarcinoma sub-type of ovarian cancer represents a completely unaddressed indication where, presently, no effective treatment modality exists.

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Abstract

La présente invention concerne des méthodes et des compositions pour traiter des sous-populations réfractaires ou résistantes aux agents de traitement du cancer à base de platine et/ou de taxanes et/ou le sous-type d'adénocarcinome mucineux de sujets atteints d'un cancer de l'ovaire avec le dérivé de la camptothécine hautement lipophile contenant du silicium (HLCD), la karénitécine (également connue sous le nom de BNP1350, cositécan, 7-[(2'-triméthylsilyl)éthyl]-20(S) camptothécine). L'invention concerne également l'administration de la karétinécine par des voies intraveineuses (i.v.) et/ou orales.
EP14836702.2A 2013-08-13 2014-08-10 Administration de karénitécine pour traiter un cancer avancé de l'ovaire, y compris des sous-types d'adénocarcinomes chimio-résistants et/ou mucineux Withdrawn EP3033150A4 (fr)

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US201361865360P 2013-08-13 2013-08-13
PCT/US2014/050463 WO2015023551A1 (fr) 2013-08-13 2014-08-10 Administration de karénitécine pour traiter un cancer avancé de l'ovaire, y compris des sous-types d'adénocarcinomes chimio-résistants et/ou mucineux

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EP3033150A1 true EP3033150A1 (fr) 2016-06-22
EP3033150A4 EP3033150A4 (fr) 2017-06-28

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WO2013067050A1 (fr) 2011-10-31 2013-05-10 University Of Utah Research Foundation Modifications génétiques dans un glioblastome
US20180301223A1 (en) * 2015-04-14 2018-10-18 University Of Utah Research Foundation Advanced Tensor Decompositions For Computational Assessment And Prediction From Data
CN105198790B (zh) * 2015-04-20 2018-02-16 范国煌 促进双阴性t细胞体外增殖的四环化合物
EP3199641B1 (fr) * 2016-01-27 2021-09-29 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Moyens et procédés permettant d'évaluer l'évolution, de saisir les données et de traiter une maladie cancéreuse
CN107058315B (zh) * 2016-12-08 2019-11-08 上海优卡迪生物医药科技有限公司 敲减人PD-1的siRNA、重组表达CAR-T载体及其构建方法和应用
AU2018289369A1 (en) * 2017-06-20 2020-01-16 Nantomics, Llc Use of cell-free circulating rna (cfRNA) expression of PD-L1 and ERCC1 in plasma to monitor response to therapy in NSCLC
CN113461952B (zh) * 2021-06-30 2022-07-01 广州市第一人民医院（广州消化疾病中心、广州医科大学附属市一人民医院、华南理工大学附属第二医院） 一种活性氧响应型自降解聚合物及其制备方法与应用
CN118103949A (zh) * 2021-09-15 2024-05-28 英飞凌科技有限责任公司 将sonos集成至hkmg流中的方法

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JP5170741B2 (ja) * 2004-04-27 2013-03-27 ウェルスタット バイオロジクス コーポレイション ウイルスおよびカンプトテシン類を使用する癌の処置
CA2632903C (fr) * 2005-12-02 2015-11-24 Vianova Labs, Inc. Traitement du cancer et d'autres maladies
US9023805B2 (en) * 2010-09-16 2015-05-05 Bionumerik Pharmaceuticals, Inc. Increasing cancer patient survival time by administration of dithio-containing compounds

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WO2015023552A1 (fr) 2015-02-19
WO2015023553A2 (fr) 2015-02-19
EP3033150A4 (fr) 2017-06-28
WO2015023553A3 (fr) 2015-04-23
WO2015023551A1 (fr) 2015-02-19

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