A Phase 1 Trial of the p97 Inhibitor CB-5339 in Patients With Advanced Solid Tumors and Lymphomas

• INCLUSION CRITERIA:

• Patients with histologically documented metastatic or locally advanced (not amenableto surgery) solid tumors whose disease has progressed on standard therapy or for whichthere is no available standard therapy or therapy known to prolong survival; oraggressive lymphoma who have refused or have no remaining curative options (e.g., stemcell transplant). Patients with indolent lymphomas must have undergone 3 or more prior 24 regimens of therapy.

• Any prior therapy must have been completed >=4 weeks (6 weeks for nitrosoureas andmitomycin C) or, if known, >=5 half-lives of the prior agent (whichever is shorter)prior to enrollment on protocol (minimum of 1 week between prior therapy and studyenrollment), and the participant must have recovered to eligibility levels from priortoxicity. Prior definitive radiation should have been completed >=4 weeks orpalliative radiation should have been completed >=2 weeks prior to study enrollmentand all associated toxicities resolved to eligibility levels (patients on study may beeligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapyat the PI s discretion). Patients must be >=2 weeks since any investigational agentadministered as part of a Phase 0 study (where a sub-therapeutic dose of drug isadministered) at the PI s discretion and should have recovered to grade 1 or baselinefrom any toxicities.

• Patients who have had prior monoclonal antibody therapy must have completed thattherapy >=6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior toenrollment on protocol (minimum of 1 week between prior therapy and study enrollment).

• Age >=18 years. Because no dosing or adverse event data are currently available on theuse of CB-5339 in patients <18 years of age, children are excluded from this study,but will be eligible for future pediatric trials.

• ECOG performance status <=2 (Karnofsky >=60%, see Appendix A) and life expectancy > 3months,

• Patients must have adequate organ and marrow function as defined below:

• absolute neutrophil count >= 1,500/mcL

• platelets >=100,000/mcL (solid tumor patients); >=75,000/mcL (lymphoma patients)

• total bilirubin <= 1.5 x institutional upper limit of normal (ULN)

• AST(SGOT)/ALT(SGPT) <=3 (SqrRoot) institutional ULN

• creatinine <= 1.5 x institutional ULN OR >=60 mL/min/1.73 m^2 for patients withcreatinine levels above 1.5X institutional normal

• The effects of CB-5339 on the developing human fetus are unknown. For this reason andbecause p97 inhibitors agents may be teratogenic, women of child-bearing potential andmen must agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry and for the duration of study participationand for 4 months afterwards. Should a woman become pregnant or suspect she is pregnantwhile she or her partner is participating in this study, she should inform hertreating physician immediately. Men treated or enrolled on this protocol must alsoagree to use adequate contraception prior to the study, for the duration of studyparticipation, and 4 months after completion of CB-5339 administration.

• Ability to understand and the willingness to sign a written informed consent document.

• Subjects on the expansion cohort must also be willing to undergo two core biopsyprocedures and have a lesion amenable to biopsy.

• Left ventricular ejection fraction (Bullet) the lower limit of normal by ECHO atentry.

• Mean QT interval corrected for heart rate (QTc) <470 ms using Fridericia's Correction.

EXCLUSION CRITERIA:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study.

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

• Patients who are receiving any other investigational agents.

• Patients with clinically significant illnesses which would compromise participation inthe study, including but not limited to active or uncontrolled infection, immunedeficiencies, Hepatitis B, Hepatitis C, active tuberculosis, uncontrolled asthma,symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiacarrhythmia, myocardial infarction within the past 6 months, cerebral vascularaccident/stroke within the past 6 months, or psychiatric illness/social situationsthat would limit compliance with study requirements.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with known brain metastases or carcinomatous meningitis are excluded fromthis clinical trial, with the exception of patients whose brain metastatic diseasestatus has remained stable for >= 4 weeks after treatment of the brain metastases.Patients on anti-seizure medications may be enrolled at the discretion of thePrincipal Investigator providing that these patients are taking non-enzyme- inducinganti-seizure medications or can be converted to these.

• Pregnant women are excluded from this study because CB-5339 may have the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother with thisagent, breastfeeding should be discontinued if the mother is treated with CB-5339.

• Current or previous history of sight-threatening retinal disease, including (but notlimited to) proliferative diabetic retinopathy, severe retinal vascular disease, andadvanced age-related macular degeneration.

• Patients with a history of QT-prolongation or of Torsades de pointes (TdP), or oftaking QT-prolonging drugs, are not eligible.