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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04449562
• Other study ID #: 200135
• Secondary ID: 20-C-0135
• Status: Recruiting
• Phase: Phase 1
• Start date: July 10, 2020
• Est. completion date: March 1, 2023

Study information

• Verified date: July 1, 2020
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Murielle Hogu
• Phone: (240) 858-3335
• Email: murielle.hogu[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

• Due to its critical role in protein homeostasis pathways, p97 is a promising target for the treatment of malignancies; tumor cells are considered to be dependent on components of the protein degradation machinery to maintain homeostasis and survive.

• The p97 inhibitor CB-5339 has been well characterized in in vitro and in vivo studies and had demonstrated induction of an unfolded protein response, decreased cell viability, and apoptosis.

Primary Objective:

-To establish the safety, tolerability, and recommended phase 2 dose (RP2D) of 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:

• To evaluate the pharmacokinetic profiles of CB-5339

• To assess the preliminary antitumor activity of CB-5339 in patients with advanced solid tumors and lymphomas

• To determine the effects of CB-5339 on the ubiquitin proteasome system and markers of cell death in pre- and post-treatment tumor biopsies and peripheral blood mononuclear cells (PBMCs)

Exploratory Objectives:

-To evaluate potential associations between CB-5339 activity and genomic alterations assessed in circulating tumor DNA

Eligibility:

Patients >= 18 years of age must have histologically documented 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. Patients with indolent lymphomas must have undergone 3 or more prior regimens of therapy

Study Design:

• CB-5339 will be administered orally on a schedule of once daily, 4 days on and 3 days off, in 28-day cycles.

• The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. A separate 15-patient expansion cohort will further explore pharmacodynamic endpoints and obtain additional pharmacokinetic data at the RP2D.

• Once pharmacodynamic data are available at the RP2D, additional expansion cohorts may be considered to explore pharmacodynamic endpoints at lower dose levels (a protocol amendment will be submitted for these changes to the trial design).

• Blood samples will be obtained for pharmacokinetic and pharmacodynamic analyses and to isolate circulating tumor DNA. Tumor biopsies will be collected at baseline and 4-6 hours after drug administration in the expansion cohort only; an optional biopsy may be collected at disease progression.

• Pharmacodynamic effects of CB-5339 will be assessed through a panel of markers including accumulation of lysine-48 (K48) specific polyubiquitinated substrates in the cytosol, upregulation of

transcription factor CHOP in nucleus, and appearance of cleaved caspase-3 in the cytosol.

Description:

Background:

• Due to its critical role in protein homeostasis pathways, p97 is a promising target for the treatment of malignancies; tumor cells are considered to be dependent on components of the protein degradation machinery to maintain homeostasis and survive.

• The p97 inhibitor CB-5339 has been well characterized in in vitro and in vivo studies and had demonstrated induction of an unfolded protein response, decreased cell viability, and apoptosis.

Primary Objective:

-To establish the safety, tolerability, and recommended phase 2 dose (RP2D) of 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:

• To evaluate the pharmacokinetic profiles of CB-5339

• To assess the preliminary antitumor activity of CB-5339 in patients with advanced solid tumors and lymphomas

• To determine the effects of CB-5339 on the ubiquitin proteasome system and markers of cell death in pre- and post-treatment tumor biopsies and peripheral blood mononuclear cells (PBMCs)

Exploratory Objectives:

-To evaluate potential associations between CB-5339 activity and genomic alterations assessed in circulating tumor DNA

Eligibility:

Patients >= 18 years of age must have histologically documented 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. Patients with indolent lymphomas must have undergone 3 or more prior regimens of therapy

Study Design:

• CB-5339 will be administered orally on a schedule of once daily, 4 days on and 3 days off, in 28-day cycles.

• The trial will follow an accelerated titration design, changing to a traditional 3+3 dose escalation design (3-6 patients per cohort) once specified toxicity criteria are met. A separate 15-patient expansion cohort will further explore pharmacodynamic endpoints and obtain additional pharmacokinetic data at the RP2D.

• Once pharmacodynamic data are available at the RP2D, additional expansion cohorts may be considered to explore pharmacodynamic endpoints at lower dose levels (a protocol amendment will be submitted for these changes to the trial design).

• Blood samples will be obtained for pharmacokinetic and pharmacodynamic analyses and to isolate circulating tumor DNA. Tumor biopsies will be collected at baseline and 4-6 hours after drug administration in the expansion cohort only; an optional biopsy may be collected at disease progression.

• Pharmacodynamic effects of CB-5339 will be assessed through a panel of markers including accumulation of lysine-48 (K48) specific polyubiquitinated substrates in the cytosol, upregulation of transcription factor CHOP in nucleus, and appearance of cleaved caspase-3 in the cytosol.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: March 1, 2023
• Est. primary completion date: March 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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 24 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 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).

• Age >=18 years. Because no dosing or adverse event data are currently available on the use 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 > 3 months,

• 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 with creatinine levels above 1.5X 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 and have a lesion amenable to biopsy.

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

Related Conditions & MeSH terms

• Advanced Lymphomas
• Advanced Solid Tumors
• Lymphoma

Intervention

Drug:
• CB-5339
Due to its critical role in protein homeostasis pathways, p97 is a promising target for the treatment of malignancies; tumor cells are considered to be dependent on components of the protein degradation machinery to maintain homeostasis and survive. The p97 inhibitor CB-5339 has been well characterized in in vitro and in vivo studies and had demonstrated induction of an unfolded protein response, decreased cell viability, and apoptosis.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss von Soly S, Madriaga A, Soriano F, Menon MK, Wu ZY, Kampmann M, Chen Y, Weissman JS, Aftab BT, Yakes FM, Shawver L, Zhou HJ, Wustrow D, Rolfe M. Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis. Cancer Cell. 2015 Nov 9;28(5):653-665. doi: 10.1016/j.ccell.2015.10.002. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To establish the safety, tolerability, and recommended phase 2 dose (RP2D) of 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	Adverse event descriptions and grading scales from the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.	cycle 1
Secondary	To evaluate the pharmacokinetic profiles of CB-5339	Measurement of levels of CB-5339 in each patient s blood and urine (i.e., metabolism) at each dose level	cycles 1 and 2
Secondary	To assess the preliminary antitumor activity of CB-5339 in patients with advanced solid tumors and lymphomas.	Measurement of changes in tumor size by CT imaging	1 year
Secondary	To determine the effects of CB-5339 on the ubiquitin proteasome system and on markers of cell death in preand post-treatment tumor biopsies and PBMCs	The pharmacodynamic effects of CB-5339 will be assessed through accumulation of lysine-48 (K48) specific polyubiquitinated substrates in the cytosol, upregulation of transcription factor CHOP in nucleus, and appearance of cleaved caspase-3 in the cytosol	cycle 1

External Links

•   NIH Clinical Center Detailed Web Page