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

Status Recruiting

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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Advanced Lymphomas
• Advanced Solid Tumors
• Lymphoma

• NCT number: NCT04449562
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Murielle Hogu
• Phone: (240) 858-3335
• Email: murielle.hogu@nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: July 10, 2020
• Completion date: March 1, 2023