PRIMARY OBJECTIVE:
I. To establish the safety, tolerability, and recommended phase 2 dose (RP2D) of p97
inhibitor CB-5339 tosylate (CB-5339) administered orally on a schedule of once daily, 4 days
on and 3 days off, in patients with advanced solid tumors and lymphomas.
SECONDARY OBJECTIVES:
I. To evaluate the pharmacokinetic profiles of CB-5339. II. To assess the preliminary
antitumor activity of CB-5339 in patients with advanced solid tumors and lymphomas.
III. To determine the effects of CB-5339 on the ubiquitin proteasome system and on markers of
cell death in pre- and post-treatment tumor biopsies and peripheral blood mononuclear cell
(PBMC)s.
EXPLORATORY OBJECTIVE:
I. To evaluate potential associations between CB-5339 activity and genomic alterations
assessed in circulating tumor deoxyribonucleic acid (DNA) (ctDNA).
OUTLINE: This is a dose-escalation study.
Patients receive p97 inhibitor CB-5339 tosylate orally (PO) once daily (QD) 4 days on and 3
days off. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up for 30 days.
Inclusion Criteria:
- Patients with histologically documented metastatic or locally advanced (not amenable
to surgery) solid tumors whose disease has progressed on standard therapy or for which
there is no available standard therapy or therapy known to prolong survival; or
aggressive lymphoma who have refused or have no remaining curative options (e.g., stem
cell transplant). Patients with indolent lymphomas must have undergone 3 or more prior
regimens of therapy
- Any prior therapy must have been completed >= 4 weeks (6 weeks for nitrosoureas and
mitomycin 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 study
enrollment), and the participant must have recovered to eligibility levels from prior
toxicity. Prior definitive radiation should have been completed >= 4 weeks or
palliative radiation should have been completed >= 2 weeks prior to study enrollment
and all associated toxicities resolved to eligibility levels (patients on study may be
eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapy
at the principal investigator [PI]'s discretion). Patients must be >= 2 weeks since
any investigational agent administered as part of a phase 0 study (where a
sub-therapeutic dose of drug is administered) at the PI's discretion and should have
recovered to grade 1 or baseline from any toxicities
- Patients who have had prior monoclonal antibody therapy must have completed that
therapy >= 6 weeks (or 3 half-lives of the antibody, whichever is shorter) prior to
enrollment on protocol (minimum of 1 week between prior therapy and study enrollment)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
and life expectancy > 3 months
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL (solid tumor patients)
- Platelets >= 75,000/mcL (lymphoma patients)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Creatinine =< 1.5 x institutional ULN OR 60 mL/min/1.73 m^2 for patients with
creatinine levels above 1.5 x institutional normal
- The effects of CB-5339 on the developing human fetus are unknown. For this reason and
because p97 inhibitors agents may be teratogenic, women of child-bearing potential and
men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation
and for 4 months afterwards. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, 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 biopsy
procedures if there is a lesion amenable to biopsy
- Left ventricular ejection fraction >= the lower limit of normal by echocardiogram
(ECHO) at entry
- 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 for
nitrosoureas 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 in
the study, including but not limited to active or uncontrolled infection, immune
deficiencies, hepatitis B, hepatitis C, active tuberculosis, uncontrolled asthma,
symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac
arrhythmia, myocardial infarction within the past 6 months, cerebral vascular
accident/stroke within the past 6 months, or psychiatric illness/social situations
that would limit compliance with study requirements.
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for >= 4 weeks after treatment of the brain metastases.
Patients on anti-seizure medications may be enrolled at the discretion of the
principal investigator providing that these patients are taking non-enzyme- inducing
anti-seizure medications or can be converted to these
- Pregnant women are excluded from this study because CB-5339 may have the potential for
teratogenic or abortifacient effects. Because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with this
agent, breastfeeding should be discontinued if the mother is treated with CB-5339
- Current or previous history of sight-threatening retinal disease, including (but not
limited to) proliferative diabetic retinopathy, severe retinal vascular disease, and
advanced age-related macular degeneration
- Patients with a history of QT-prolongation or of Torsades de pointes (TdP), or of
taking QT-prolonging drugs, are not eligible
