Phase 1 Safety Study of ACT-PFK-158, 2HCl in Patients With Advanced Solid Malignancies

Inclusion Criteria

• Histological or cytological evidence of solid malignancy.
• Patients must have:
• a. Have advanced solid tumors that are refractory to established therapies known to provide clinical benefit for the malignancy in question, OR
• b. Be intolerant of established therapies known to provide clinical benefit for the malignancy in question
• Patients enrolled in the dose-expansion part of the trial must have at least one lesion that may qualify as a target lesion based on the RECIST 1.1 criteria.
• Patient is ambulatory with an ECOG performance status of 0, 1 or 2 and an estimated life expectancy of > 3 months.
• Patient is 18 years and older.
• Patients or their legal representatives must have the ability to read, understand and provide written informed consent for the initiation of any study related procedures.
• Patients must have adequate bone marrow reserve as evidenced by:
• a. WBC > 3,000/µL
• b. Absolute neutrophil count (ANC) ≥ 1,500/µL
• c. Platelet count ≥ 100,000/µL
• d. Hemoglobin ≥ 9 gm/dL.
• Patients must have adequate renal function as evidenced by a serum creatinine ≤ 1.5 X ULN for the reference laboratory OR a calculated creatinine clearance of ≥ 60 mL/min by the Cockroft-Gault equation.
• Patients must have adequate hepatic function as evidenced by AST and ALT values ≤ 3 X ULN (≤ 5 X ULN if the liver is known to be involved by metastatic disease) and serum total bilirubin values of ≤ 1.5 X ULN for the reference laboratory.
• Patients must have INR and PTT values ≤ 1.5X ULN for the reference laboratory.
• Patients must be recovered from the effects of any prior chemotherapy, radiotherapy or surgery (i.e., toxicity no worse than Grade 1); for patients who have been on monoclonal antibody therapy, at least one half-life or 4 weeks (whichever is shorter) should have elapsed prior to the first scheduled day of dosing with PFK-158.
• Patients on prior investigational agents must wait at least 5 half-lives before enrollment into the trial, or 4 weeks if the half-life of the investigational agent is not known.
• Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment.
• Women of childbearing potential and men with female sexual partners of childbearing potential must agree to use an effective method of contraception (e.g., oral contraceptives, double-barrier methods such as a condom and a diaphragm, intrauterine device) during the study and for 90 days following the last dose of study medication or to abstain from sexual intercourse for this time; a woman not of childbearing potential is one who has undergone bilateral oophorectomies or who is post-menopausal, defined as no menstrual periods for 12 consecutive months.

Exclusion Criteria

• Patients with an active infection or with a fever ≥ 38.5°C within 3 days of the first scheduled day of dosing.
• Patients with primary CNS tumors as well as patients with CNS metastases are excluded.
• Patients with known hypersensitivity to any of the components of PFK-158.
• Patients who are receiving investigational therapies or who have been treated with investigational therapies or investigational devices within 5 half-lives of the investigational therapy or 4 weeks of first scheduled day of dosing with PFK-158 if the half-live of the investigational agent is not known.
• Uncontrolled hypertension as defined by SBP > 160 mm/Hg or DBP > 100 mm/Hg despite medical therapy.
• Subjects with diabetes.
• Patients who require pharmacologic doses of corticosteroids; replacement, topical, ophthalmologic and inhalational steroids are permitted.
• Patients who require coumadin administration.
• Patients with mean QTcF values of > 470 msec (in females) or > 450 msec (in males) following 3 ECGs conducted 5 minutes apart from each other; patients who are known to have congenital prolonged QT syndromes; or patients who are on medications known to cause prolonged QT intervals on ECG.
• Patients with clinically significant cardiovascular co-morbidities including: congestive heart failure (New York Heart Association class III-IV heart disease), unstable angina pectoris, cardiac arrhythmias requiring medication or a pacemaker; myocardial infarction within the past six months; stroke within the past 6 months; or hypertension requiring more than 2 medications for blood pressure control.
• Patients with any other concurrent uncontrolled illness, including mental illness or substance abuse, which may interfere with the ability of the patient to cooperate and participate in the trial; other examples of such conditions would include COPD or diabetes mellitus that has required 2 or more hospitalizations in the last year; severe peripheral vascular disease; poorly controlled auto-immune conditions; recent serious trauma.
• Grade 2 or higher peripheral neuropathy.
• Patients currently known to be positive for, HIV, hepatitis B or C.
• Patients who are pregnant or lactating.
• Concurrent or recent (within 1 month) use of thrombolytic agents, or full-dose anticoagulants (except to maintain patency of preexisting, permanent indwelling IV catheters). Of note, therapy with low-molecular weight heparin is acceptable as long as the INR < 2.0.
• Significant traumatic injury within the past 4 weeks.
• Patients who are in-patients.