Study of NK012 and Carboplatin in Solid Tumors With Dose Expansion in Triple Negative Breast Cancer

NK012 will be administered as a 30 minute IV infusion, followed by a 30 minute carboplatin IV infusion. Both drugs will be administered once every 28 days. Treatment is expected to continue for 6 cycles, unless disease progression or the development of unacceptable toxicity requires discontinuation of the drug. At the discretion of the investigator, patients who show signs of benefit may continue beyond 6 cycles.

Once a MTD/RD has been determined, a dose expansion cohort of patients with metastatic triple negative breast cancer will be treated at the determined MTD.

Inclusion criteria

• Histologically or cytologically confirmed diagnosis of advanced solid tumor for which no efficacious therapy exists, or for which a camptothecin-based regimen would be appropriate.
• For the dose expansion at the MTD/RD only:

• Patients must have triple-negative breast cancer with locally advanced disease for which there is no surgical option, or stage IV disease. Triple-negative breast cancer is defined as HER2-negative, ER-negative, and PR-negative as follows:

For HER2- negative (must meet one of the following 3):

( i) FISH negative (ratio <2.2); or ( ii) IHC 0 or 1+; or (iii) IHC 2+ or 3+ and FISH negative (ratio <2.2) For ER negative and PR negative: ≤ 10% tumor staining by IHC

• No less than one and no more than two prior chemotherapy regimens for advanced or metastatic breast cancer.
• Patients must have measurable disease by RECIST (version 1.1).
• Patients must have recovered from all acute adverse effects of prior therapies, excluding alopecia.
• For patients enrolled in the dose escalation phase, no more than 4 prior cytotoxic regimens in the metastatic setting.
• Prior irradiation to no more than 25% of the bone marrow.
• ECOG performance status of 0 or 1.
• Life expectancy of at least 12 weeks.
• Patients are at least 18 years of age.
• Adequate bone marrow function defined as ANC ≥ 1500/mm^3 and platelet count ≥ 100,000/mm^3.
• AST and ALT ≤ 3.0 x ULN (5X ULN if documented liver metastases) and total bilirubin ≤ 1.5 x ULN.
• Serum creatinine < 1.5 x ULN, or creatinine clearance > 60 mL/min by Cockcroft-Gault formula* for patients with serum creatinine > 1.5x ULN.

• Cockcroft-Gault formula for creatinine clearance (CrCl): Males: CrCl (ml/min) = (140 - age) x wt (kg) / (serum creatinine x 72) Females: Multiply the above result by 0.85
• Able to understand and show willingness to sign a written informed consent document.

Exclusion criteria

• Prior chemotherapy, radiation therapy, or investigational therapy within 4 weeks (exception: 6 weeks for nitrosoureas or mitomycin C); or prior non-cytotoxic therapy within 5 drug half-lives (or 4 weeks, which ever is shorter); or monoclonal antibodies within 4 weeks prior to the first dose of study treatment.
• Concurrent use of another investigational agent.
• History of brain metastases or spinal cord compression, unless irradiated or treated a minimum of 4 weeks prior to first study treatment and stable without requirement of corticosteroids for > 1 week.
• Concurrent serious infections requiring parenteral antibiotic therapy.
• Pregnant or of childbearing potential and not using methods to avoid pregnancy. A negative pregnancy test must be documented at baseline for women of child-bearing potential. Patients may not breast feed infants while on this study.
• Significant cardiac disease including heart failure that meets NYHA class III and IV definitions, history of myocardial infarction within 6 months of study entry, uncontrolled dysrhythmias or poorly controlled angina.
• History of serious ventricular arrhythmia (VT or VF, ≥ 3 beats in a row), QTc ≥ 450 msec for men and 470 msec for women, or LVEF ≤ 40% by MUGA or ECHO.
• History of allergic reactions attributed to compounds of topoisomerase I inhibitors, or platinum-containing compounds.
• Prior treatment with irinotecan.
• Prior treatment with more than 6 cycles of platinum drugs.