NZ619009B2 - Medicaments and methods for treating cancer - Google Patents

Abstract

Provided are compositions comprising sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)], and uses of these in the treatment of cancer. The compositions involve the delivery of 400-1562.5 mg or 320-625 mg/m2 of the compound based on the body surface area of the patient, and contain a reduced amount of indazolium hydrochloride. The dosage range is based on the minimum effective dose and maximal tolerated dose of the compound. Further provided is the use of the compound in the treatment of cancer by particular administration schedules, and with the administration of a drug to prevent infusional fever which can be a side effect of intravenous sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] administration. mount of indazolium hydrochloride. The dosage range is based on the minimum effective dose and maximal tolerated dose of the compound. Further provided is the use of the compound in the treatment of cancer by particular administration schedules, and with the administration of a drug to prevent infusional fever which can be a side effect of intravenous sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] administration.

Description

MEDICAMENTS AND METHODS FOR TREATING CANCER CROSS-REFERENCE TO US APPLICATIONS The application claims priority to US Provisional Application No. 61/486,783 which is incorporated herein by reference.

FIELD OF THE INVENTION This invention generally relates to a dosing regimen and dosing units comprising sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)]. Methods of treating cancer are described herein.

BACKGROUND OF THE INVENTION A number of ruthenate compounds are known in the art to be useful as antitumor compounds. See e.g., US Patent No. 4,843,069; PCT Publication No. WO 9736595, and US Application Publication No. 2005032801. In particular, the ruthenium complex salts indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] and sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] have been shown to be highly potent in inducing apoptosis in certain types of cancer. See U.S. Patent No. 7,338,946.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

SUMMARY OF THE INVENTION The present invention is at least in part based on the discovery of a minimum effective dose and a maximal tolerated dose of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] administered to a patient for treating cancer. The present invention is at least in part based on the discovery of a superior dosing schedule for intravenously administering sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to a patient for treating cancer. 2 Accordingly, in a first aspect, the present invention provides a pharmaceutical unit dosage form having greater than 400 mg of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)], wherein the molar ratio of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1. Preferably, the pharmaceutical unit dosage form has from about 600 to about 1000 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] and is substantially free of indazolium hydrochloride. Also preferably the pharmaceutical unit dosage form contains from about 650 to about 1000 mg of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)]. The pharmaceutical unit dosage forms may be, e.g., lyophilized powder in a vial.

The invention also provides a pharmaceutical unit dosage form having from 320 mg/m2 to 625 mg/m2 of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)], based on the body surface area (BSA) of a patient, wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1.

Relevant to this aspect, a medicament is also provided having from 600 mg to 1600 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)], wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1.

In another aspect, the present invention provides use of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein said medicament comprises an amount of from 400 mg to 1562.5 mg of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)].

In another aspect, the present invention provides use of a therapeutically effective amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein said medicament is to be administered intravenously, on a dosing schedule of once a week, and wherein said medicament is to be administered once on each day 1, day 8 and day 15 of a 28-day or monthly cycle, and wherein said medicament is to be administered at an amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] of at least 320 mg/m2 based on the body surface area (BSA) of said patient.

In another aspect, the present invention provides use of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for 3 use in the treatment of cancer in a patient, wherein said medicament is to be administered at an amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] from 320 mg/m2 to 625 mg/m2 based on the body surface area (BSA) of said patient.

In another aspect, the present invention provides use of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein a medication for preventing infusional fever is to be administered to said patient prior to the administration of said medicament.

Described herein is a method of treating cancer comprising administering a pharmaceutical composition comprising sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] intravenously to a patient in need of treatment of cancer at an amount of from greater than about 500 mg to about 1562.5 mg, preferably at an amount greater than about 600 mg. Also preferably, the pharmaceutical composition is substantially free of indazolium hydrochloride. In some embodiments, the sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] is administered once a week, preferably once on each day 1, day 8 and day 15 of a 28-day or monthly cycle.

Described herein is a method of treating cancer comprising administering a therapeutically effective amount of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] to a patient in need of treatment of cancer, intravenously on a dosing schedule of once a week, preferably on each day 1, day 8 and day 15 of a 28- day or monthly cycle. Preferably, sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] is administered at an amount of at least about 320 mg/m2 based on the body surface area (BSA) of the patient, preferably at an amount of from about 320 mg/m2 to about 625 mg/m2 based on the body surface area (BSA) of the patient.

Described herein is a method of treating cancer comprising administering to a patient in need of treatment the compound sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] at an amount from about 320 mg/m2 to about 625 mg/m2 based on the body surface area (BSA) of the patient, preferably through intravenous infusion.

Described herein is a method for treating cancer comprising administering to a patient a medication for preventing infusional fever prior to the administration of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] intravenously to the patient.

The fever-preventing drug may be a steroid such as prednisone or dexamethasone. 4 The foregoing and other advantages and features of the invention, and the manner in which the same are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying examples, which illustrate exemplary embodiments.

In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the PK curves arranged from the bottom to the top correspond to drug doses of 20 mg/m2 , 40 mg/m2 , 80 mg/m2 , 160 mg/m2 , 320 mg/m2 and 420 mg/m2 , respectively; Figure 2: Total ruthenium levels measured by ICP-MS. A) Plasma ruthenium levels for Cycle 1 Day 1 (C1D1), Cycle 1 Day 8 (C1D8) and Cycle 2 Day 1 (C2D1); B) drug dose proportionality of Cmax; C) drug dose proportionality AUC0-24.

DETAILED DESCRIPTION OF THE INVENTION Described herein is a method of treating cancer, comprising administering a therapeutically effective amount of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] to a patient in need of treatment of cancer, intravenously on a dosing schedule of once a week. Preferably, the sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] is in a pharmaceutical composition substantially free of indazolium hydrochloride. As used herein and in the description below, the term “substantially free of indazolium hydrochloride” means that in the pharmaceutical composition the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 4 to 1. In preferred embodiments, the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 10:1 or greater, and more preferably 20:1 or greater.

In some embodiments, sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] is administered each time at an amount of at least about 400 or 500 mg, or at least about 320 mg/m2 based on the body surface area (BSA) of the patient. In 5 preferred embodiments, the patient is administered once on each of day 1, day 8 and day 15 of a 28-day cycle, preferably each at an amount of at least about 320 mg/m2 based on the body surface area (BSA) of the patient, or at an absolute amount of at least about 400 or 500 mg. The BSA can be calculated using the Modified Dubois, i.e., BSA (m²) = 0.007184 x Height(cm)0.725 x Weight(kg)0.425.

In preferred embodiments, the amount of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] administered to a patient at each administration, e.g., in the one time on day 1, is at least about 320 mg/m2 , preferably between about 320 mg/m2 and about 625 mg/m2 .

The dosage range of from about 320 mg/m2 and about 625 mg/m2 was discovered during a human dose escalating clinical trial, from which 320 mg/m2 was determined to be the minimum effective dosage for general use of treating cancer while 625 mg/m2 was the maximal tolerated dose.

Thus, described herein is a method of treating cancer, comprising administering intravenously to a patient in need of treatment of cancer sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] at an amount of at least about 320 mg/m2 , preferably between about 320 mg/m2 and about 625 mg/m2 based on the patient’s BSA. The BSA of normal adults typically ranges from 1.5 to about 2.5 m2 . Thus, in some embodiments, a method of treating cancer comprises administering intravenously to a patient in need of treatment of cancer sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] at an amount of about 400 mg to about 1600 mg, or about 400 mg to about 1500 mg, or about 400 mg to about 1400 mg, or about 400 mg to about 1200 mg, preferably 480 mg to about 1600 mg, 500 mg to about 1562.5 mg, preferably an amount that is greater than about 600 mg but preferably less than about 1600 mg. Preferably, sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] is administered in a pharmaceutical composition that is substantially free of indazole hydrochloride. Preferably the pharmaceutical composition is administered once a week, and preferably once on each of day 1, day 8 and day 15 of a 28-day cycle. In some embodiments, sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] is intravenously administered in an amount of greater than 600 mg, e.g., from greater than 600 mg to about 1200 mg. For example, in preferred embodiments, an amount of from greater than 600 mg to about 1200 or 1400 mg is administered intravenously once a week, or according to the following schedule: from greater than 600 mg to about 1200 or 1400 mg on day 1, 6 from greater than 600 mg to about 1200 or 1400 mg on day 8, and from greater than 600 mg to about 1200 or 1400 mg on day 15 of a 28-day or monthly cycle. That is, after one 28-day or a month period, in which a patient is administered from greater than 600 mg to about 1200 or 1400 mg on days 1, 8 and 15 of that 28-day period, the same amount is administered to the patient on days 1, 8, and 15 of the next 28-day period, and repeating the administration cycle if necessary. In preferred embodiments, the sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] is in a pharmaceutical composition substantially free of indazolium hydrochloride.

Also described herein is a method of treating cancer, comprising administering intravenously to a patient in need of treatment of cancer sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] at an amount sufficient to arrive at a plasma Cmax of at least about 30 µg/ml and/or a plasma AUC0-192 (AUC within the period of 192 hours after administration) of at least 2500 µg/ml. hr as measured by ruthenium (III). Preferably, the amount of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] is administered such that the plasma Cmax is less than about 50 µg/ml and/or a plasma AUC0-192 (AUC within the period of 192 hours after administration) of less than about 4500 µg/ml. hr as measured by ruthenium (III).

Figures 1-2 show the pharmacokinetics behavior of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] in patients. In preferred embodiments, the sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] is in a pharmaceutical composition substantially free of indazolium hydrochloride.

Sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] can be made in any methods known in the art. For example, PCT Publication No. WO/2008/154553 discloses an efficient method of making sodium trans-[tetrachlorobis(1Hindazole)ruthenate(III)].

Described herein is a use of sodium trans-[tetrachlorobis(1Hindazole)ruthenate(III)] at an amount of from about 400 mg to about 1200 mg, about 1500 mg or about 2000 mg, preferably from more than 500 mg to about 1000 mg or 1200 mg, more preferably from about 600 mg or 650 mg to about 1000 mg or 1200 mg for the manufacture of an intravenously injectable medicament useful for treating cancer. Injectable forms are generally known in the art, e.g., in buffered solution or suspension.

In another aspect, the present invention provides a pharmaceutical unit dosage form having greater than about 500 mg of sodium trans-[tetrachlorobis(1H- 7 indazole)ruthenate (III)] and is substantially free of indazolium hydrochloride.

Preferably, the pharmaceutical unit dosage form has from about 600 mg or 650 mg to about 1600 mg, preferably from about 600 to about 1000 mg of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] and is substantially free of indazolium hydrochloride. The pharmaceutical unit dosage forms may be, e.g., lyophilized powder in a vial. A medicament is also provided having from about 600 mg to about 1600 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)].

It has been discovered that at therapeutically effective doses, intravenous infusion of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] is associated with a higher incidence of fever or chill, which can be prevented by premedication with steroids. Thus, in another aspect, a method is provided for treating cancer comprising administering to a patient a medication effective for preventing or reducing infusional fever, and thereafter administering a therapeutically effective amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)]. The interval between the two different administrations may be from 0 to about 2 hours, preferably between 30 minutes and 1 hour. To put it differently, the invention provides the use of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for treating a cancer patient who has been treated with a medication effective for preventing or reducing infusional fever, e.g., within the previous 30 minutes to about 2 hours. Medications for preventing or ameliorating fever are known in the art. Steroids are most often used, e.g., prednisone and dexamethasone, which are well known drugs, and a skilled artisans should know how to administer such drugs for purposes of preventing or reducing fever. For example, dexamethasone may be administered IV at an amount of 4-10 mg. Additional premedications such as 5HT3 antagonists (serotonin antagonists) like ondansetron and granisetron may also be administered prior to the administration of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)].

Described herein is a method of treating head and neck cancer, particularly head and neck carcinoma, comprising administering to a patient in need of treatment an effective amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)]. In one embodiment, the head and neck cancer patient has previously been treated with a platinum agent, e.g., carboplatin, and/or a taxane (e.g., paclitaxel, docetaxel). The patient may be resistant to, or refractory to, such other agents. The amount of sodium 8 trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to be used may be according to the amount described herein.

EXAMPLE Two Phase I dose-escalation clinical studies involving sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] (“test drug”) have been conducted. The primary objective of both studies is to determine the safety, tolerability and maximal tolerated dose (MTD) of the test drug. Secondary objectives are to estimate the PK parameters, to identify any preliminary evidence of anti-tumor activity of the test drug in patients with advanced cancers, and to explore pharmacodynamic (PD) endpoints which may be of use in the further development of the test drug.

In the first trial which has been conducted in two centers in the US, the “test drug” was given intravenously once a week, i.e., on days 1, 8, and 15 of each 28-day cycle to patients with advanced solid tumors refractory to treatment. The patients had advanced solid tumors that had been heavily treated previously, had failed an average of 7 previous lines of chemotherapy, and had progressing disease at the time of entry into the trial. Standard 3 + 3 design with expanded cohort up to 25 patients at the maximal tolerated dose (MTD).

Major Inclusion / Exclusion Criteria: • Patients ≥ 18 years with histologically or cytologically confirmed advanced solid tumors refractory to standard therapies • ECOG PS 0 or 1 • Adequate hematologic, hepatic and renal function • No symptomatic CNS metastases, no primary brain tumors • No evidence of ischemia, recent MI, or significant abnormality on ECG • No Peripheral neuropathy ≥ Grade 2 • Minimum life expectancy ≥ 12 weeks Definition of Dose Limiting Toxicity (DLT): Toxicity severity graded according to the CTCAE (ver. 3.0); occurring during Cycle 1 and related to test drug: • Grade 4 neutropenia for ≥ 7 days • Febrile neutropenia • Grade 4 thrombocytopenia or Grade • > Grade 2 neurotoxicity • ≥ Grade 2 cardiotoxicity • Grade 2 hypersensitivity reaction or infusion reaction • Any other non-hematologic Grade 3 or 4 toxicity other than nausea/vomiting or alopecia 9 • Inability to complete the first cycle due to any toxicity thought to be related to test drug.

The demographics of the patients enrolled are summarized in Table 1 below: Table 1 Patients enrolled to date N = 46 Gender Male / Female 25 / 21 Age, years Median (Range) 61 years (28 - 78 years) Race Caucasian / Black / Other 42 / 3 / 1 Number of prior systemic therapies Median (Range) Unknown 4 (0 - 8)* 14 Tumor type CRC 11 Thymic 1 NSCLC 9 Sarcoma 1 Neuroendocri ne (NET) 5 SCLC 1 H&N 4 Adrenal 1 Breast 3 Cholangiocarcinoma 1 Pancreatic 2 Cervical 1 Ovarian 2 Unknown primasy 1 GE Junction 2 Table 2 summarizes the patients enrolled.

Table 2 Enrollment Dose level (mg/m2 ) Patients dosed Patients w/ DLT Patients replaced in due to PD in Cycle 1 1 40 1 80 1 160 1 320 7 1 1 420 5 2 500 3 625 6 1 10 780 9 3 1 Expanded Cohort (625) 12 NA DLT dose was set at 780 mg/m2 and MTD was set at 625 mg/m2 due to the dose limiting toxicity seen in 3 patients at the 780 mg/m2 dose level: Table 3: DLT Seen at 780 mg/m2 780 mg/m2 A 78 year old female had Grade 2 nausea, Grade 1 vomiting, Grade 1 fatigue following Cycle 1 Day 1 dosing associated with a Grade 2 creatinine elevation which returned to baseline within 1 week. 69 year old female had Grade 3 vomiting and Grade 3 dehydration following Cycle 1 Day 1 dosing associated with Grade 2 creatinine elevation which returned to baseline within 3 weeks.

A 53 year old male had an infusion reaction consisting of fever and chills. He had not been premedicated with steroids 36 pts completed ≥ one cycle of therapy and are evaluable to assess antitumor efficacy. In this heavily pretreated population, efficacy was assessed by partial response or stable disease for ≥ 12 weeks. All patients had PD at study entry. Table 4 summarizes the patients who had response (either partial response (PR) or stable disease (SD)).

Table 4 Dose level (mg/m 2 ) Total drug (mg) Primary Tumor Type # of Prior systemic therapies Response Duration of therapy 320 531 NSCLC 7 SD 16 weeks 320 630 NET 3 PR 100+ weeks 320 618 NSCLC 4 SD 16 weeks 420 832 NET 0* SD 24 weeks 500 890 Unknown primary 2 SD 22 weeks 625 1175 GE Junction 3 SD 12 + weeks 625 1190 CRC 3 SD 12 weeks 780 1450 Sarcoma 3 SD 16 weeks 11 780 1544 NET 1 SD 27+ weeks *Failed 4 prior chemo- and Yttrium-embolization procedures The second trial was conducted in two centers in the United Kingdom (UK) with the test drug being administered on days 1 through 4 of each 21-day cycle to patients with advanced solid tumors refractory to treatment. The patients had been heavily pretreated and had failed an average of 3 previous lines of chemotherapy. Dose escalation progressed from 20 to 500 mg/m2 .

Table 5 sums up the detailed results in the UK trial.

Table 5 Patient* # Dose mg/m2 Tumor # weeks of treatment Anti-tumor effect (best response)) 1 20 Esophageal 2 PD 2 40 Head & Neck 4 Stable disease 3 80 Mesothelioma 2 PD 4 160 Cecum 2 PD 320 Anal 1 PD 6 500 Rectal 4 Stable disease 7 500 Esophageal 2 PD As can be seen in Tables 4 and 5, stable disease was achieved in a large number of heavily pretreated patients. In particular, tumor regression was seen in the US trial in a carcinoid tumor patient who had been heavily treated with various chemotherapeutics, and had failed all such prior treatment. Sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] was administered at 320 mg/m2 on day 1, day 8 & day 15 of each 28-day cycle to the patient with stage IV carcinoid tumor of small intestine. CT scan of target lesions was performed at baseline (BL) and end of every second cycle. The patient has been treated for over 100 weeks as of today, and the scans confirmed tumor regression and partial response. The patient still remains in the trial on the test drug as no tumor progression has occurred as of today. No major adverse event related to the test drug has been seen. 12 Head & Neck Patient: Among the treated patients was a 72 year old white male with head & neck carcinoma, adenocystic histology, completely resected in April 2003.

This was Initial therapy consisted of radiotherapy (total dose 64 Gy) to the soft palate between May 2003 and July 2003 after which he achieved a partial response.

Between October 2008 and February 2009, he received 6 cycles of carboplatin and paclitaxel with best response stable disease. Upon disease progression, therapy with carboplatin and paclitaxel was resumed with the addition of reolysin June 2009 through August 2009. His best response was progressive disease. The test drug was administered at 40 mg/m2 on days 1 through 4 of each 21-day cycle. The treatment was initiated January 2010. The patient received 4 cycles of the test drug and stable disease was achieved in the patient.

Premedication: At the dose of 320 mg/m2 and above, adverse reactions such as fever and chill were seen in the UK trial. Thereafter, in the US trial, in some patients, premedication of decadron (dexamethasone) was administered, with or without 5HT3 antagonists (serotonin antagonists) like ondansetron and granisetron.

The decadron was given to prevent fever, at 4-10 mg IV. It was found that decadron was effective in preventing infusional fever. None of the patients premedicated with decadron had any incidence of infusion-related fever. In contrast, patients without premedication had a high likelihood of infusional fever. See Table 6 below.

Table 6 dosage steroid premedication no steroid premedication # of patients # with fever # of patients # with fever 320 mg/m2 4 0 3 0 420 mg/m2 2 0 3 2* 500 mg/m2 2 0 1 1 625 mg/m2 10 0 8 1 780 mg/m2 6 0 3 1 *one with no premeds, the one had fever but then none after premed of additional doses 13 Pharmacokinetics: PK samples were obtained 0, 0.25, 0.5, 1, 2, 4, 6-8, 10-12, and 24 hours after the start of the infusion on Cycle 1 Day 1 as well as pre-infusion on Cycle 1 Day 8 and Cycle 2 Day 1. Plasma and urine were analyzed for total ruthenium [Ru] (free and bound). Selected PK data is provided in Tables 7 and 8.

Figure 1 shows the plasma Ru levels over an extended period of time for doses of up to 420 mg/m2 . Peak plasma Ru levels were achieved by hour 2 (Figure 2A). There is accumulation of Ru following dosing noted by Cycle 1 Day 8 and Cycle 2 Day 1 levels. The estimated T½ is 91.4-112 hours.

Table 7: Selected PK Concentrations and Trough Values for the test drug Dose Level C1D1 Hour 24 ng/mL Ru C1D8 Hour 0 ng/mL Ru C2D1 Hour 0 ng/mL Ru mg/m2 1366 528 670 40 mg/m2 2884 1197 1472 80 mg/m2 4831 ND ND 160 mg/m2 4639 4000 6588 320 mg/m2 20033 7667 10126 420 mg/m2 25921 9595 14698 500 mg/m2 28070 11880 13000 625 mg/m2 35216 12303 14363 780 mg/m2 43105 17001 22125 There is good dose proportionality of Cmax and AUC0-168 (Table 8 and Figure 2 B, C).

In the 24 hours following Cycle 1 Day 1 dosing, there is low urinary excretion of the test drug derived ruthenium.

Table 8: Ru Cmax, Tmax and AUC0-168 values for the test drug Dose Cmax (ng/mL) (SD) Tmax (hr) (SD) AUC0-168 (hr*ng/mL) (SD) % of Dose Excreted in 24 hr1 (SD) mg/m2 2111 (na) 2.0 (na) 175400 (na) BLQ 40 mg/m2 4055 (na) 0.5 (na) 366500 (na) BLQ 80 mg/m2 8292 (na) 0.5 (na) 382300 (na) BLQ 160 mg/m2 16180 (na) 0.5 (na) 808200 (na) BLQ 320 mg/m2 32350 (6516) 1.57 (1.24) 2328000 (544800) 0.132 (0.051) 420 mg/m2 42020 (12150) 2.5 (2.6) 3331000 (743300) 0.117 (0.042) 500 mg/m2 49760 3674000 625 mg/m2 53220 4403000 780 mg/m2 71010 5516000 1 % of dose excreted in first 24 hr after Dose 1, Cycle 1 14 na: n=1, SD value not applicable BLQ: Below the Limit of Quantitation; amount excreted too low to be detected All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification and claims which include “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise” and “comprised” are to be interpreted in a similar manner.

Claims (16)

1. What we claim is: 1. A pharmaceutical unit dosage form having greater than 400 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)], wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1.
2. 2. The pharmaceutical unit dosage form of claim 1 having greater than 500 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)].
3. 3. The pharmaceutical unit dosage form of claim 1, wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 10 : 1 or greater.
4. 4. The pharmaceutical unit dosage form of claim 1, wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 20 : 1 or greater.
5. 5. The pharmaceutical unit dosage form of claim 1 having greater than 400 mg to 1600 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)].
6. 6. The pharmaceutical unit dosage form of claim 1 having from 600 to 1000 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)].
7. 7. The pharmaceutical unit dosage form of claim 1 having from 650 to 1000 mg of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)].
8. 8. The pharmaceutical unit dosage form of any one of claims 1 - 7, wherein said unit dosage form is lyophilized powder in a vial.
9. 9. A pharmaceutical unit dosage form having from 320 mg/m2 to 625 mg/m2 of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)], based on the body surface 16 area (BSA) of a patient, wherein the molar ratio of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1.
10. 10. The pharmaceutical unit dosage form of claim 9, wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 10 : 1 or greater.
11. 11. The pharmaceutical unit dosage form of claim 9, wherein the molar ratio of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 20 : 1 or greater.
12. 12. A medicament having from 600 mg to 1600 mg of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)], wherein the molar ratio of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 4 : 1.
13. 13. The medicament of claim 12, wherein the molar ratio of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 10 : 1 or greater.
14. 14. The medicament of claim 12, wherein the molar ratio of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] to indazolium hydrochloride is at least 20 : 1 or greater.
15. 15. Use of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein said medicament comprises an amount of from 400 mg to 1562.5 mg of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)].
16. 16. Use according to claim 15 wherein said medicament comprises an amount of greater than 500 mg to 1562.5 mg of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)]. 17 17. Use according to claim 15 or 16, wherein said medicament is to be administered intravenously to the patient. 18. Use according to any one of claims 15 to 17, wherein said medicament is to be administered once a week to the patient. 19. Use according to claim 18, wherein said medicament is to be administered to the patient once on each day 1, day 8 and day 15 of a 28-day or monthly cycle. 20. Use of a therapeutically effective amount of sodium trans-[tetrachlorobis(1Hindazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein said medicament is to be administered intravenously, on a dosing schedule of once a week, and wherein said medicament is to be administered once on each day 1, day 8 and day 15 of a 28-day or monthly cycle, and wherein said medicament is to be administered at an amount of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] of at least 320 mg/m2 based on the body surface area (BSA) of said patient. 21. Use according to claim 20, wherein said medicament is to be administered at an amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] from 320 mg/m2 to 625 mg/m2 based on the body surface area (BSA) of said patient. 22. Use of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein said medicament is to be administered at an amount of sodium trans- [tetrachlorobis(1H-indazole)ruthenate (III)] from 320 mg/m2 to 625 mg/m2 based on the body surface area (BSA) of said patient. 23. Use according to claim 22, wherein said medicament is to be administered intravenously. 24. Use of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] for the manufacture of a medicament for use in the treatment of cancer in a patient, wherein a 18 medication for preventing infusional fever is to be administered to said patient prior to the administration of said medicament. 25. Use according to claim 24, wherein said medication for preventing infusional fever is a steroid. 26. Use according to claim 25, wherein said steroid is dexamethasone. 27. Use according to any one of claims 24 to 26, wherein said medicament is to be administered at an amount of sodium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] from 320 mg/m2 to 625 mg/m2 based on the body surface area (BSA) of said patient. 29. A pharmaceutical unit dosage form according to any one of claims 1 to 11 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. 30. A medicament according to any one of claims 12 to 14 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures. 31. Use according to any one of claims 15 to 27 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.