A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas

• ClinicalTrials.gov Identifier: NCT02395601
• Recruitment Status: Completed
• First Posted: March 23, 2015
• Last Update Posted: September 6, 2019
• Sponsor: Constellation Pharmaceuticals
• Information provided by (Responsible Party): Constellation Pharmaceuticals

Study Description

Brief Summary:

First in human, open-label, sequential dose escalation and expansion study of CPI-1205 in patients with progressive B-cell lymphomas. CPI-1205 is a small molecule inhibitor of EZH2.

Condition or disease	Intervention/treatment	Phase
B-Cell Lymphoma	Drug: CPI-1205	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of CPI-1205, a Small Molecule Inhibitor of EZH2, in Patients With B-Cell Lymphomas
• Study Start Date: March 2015
• Actual Primary Completion Date: December 2018
• Actual Study Completion Date: December 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: CPI-1205	Drug: CPI-1205; Small molecule inhibitor of the enzyme EZH2

Outcome Measures

Primary Outcome Measures :

1. Frequency of Dose-limiting toxicities (DLTs) [ Time Frame: DLTs asessed during Cycle 1 (first 28 days on study) ]
   Frequency of dose-limiting toxicities (DLTs) associated with CPI-1205 administration during the first cycle (first 28 days) of treatment

Secondary Outcome Measures :

1. Frequency of adverse events [ Time Frame: Assessed from Day 1 of Cycle 1 through 30 days after patient's last dose of study drug ]
   Safety and tolerability of CPI-1205 as assessed by: frequency of adverse events and serious adverse events; changes in hematology and clinical chemistry values; changes in physical examination, vital signs, electrocardiogram, and ECOG score
2. Pharmacokinetic parameters of CPI-1205: AUC(0-t), AUC(0-inf), AUCtau,ss, Tmax, Cmax, Ctrough, T1/2, Vd/F, CL/F [ Time Frame: Assessed during cycle 1 (first 28 days on study); and on cycle 2, day 1 ]
3. Pharmacodynamic effects of CPI-1205 in lymphoma tissue: changes in levels of the trimethylated form of lysine residue 27 on histone 3; changes in the expression of genes whose transcription may be altered by EZH2 inhibition [ Time Frame: Assessed during cycle 1 (first 28 days on study) ]
4. Pharmacodynamic effects of CPI-1205 in bone marrow and in skin: changes in global levels of the trimethylated form of lysine residue 27 on histone 3 (H3K27me3) [ Time Frame: Assessed during cycle 1 (first 28 days on study) ]
5. Disease response assessment will be performed using the 2014 Lugano Response Criteria for Hodgkin and Non-Hodgkin Lymphoma [ Time Frame: After every 2 cycles of treatment for the first 6 cycles, and after every 4 cycles thereafter ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Adults (aged ≥ 18 years)

Histologically confirmed diagnosis of a B-cell lymphoma that has progressed in spite of prior treatment, and for which additional effective standard therapy is not available

Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

Adequate hematological, renal, hepatic, and coagulation laboratory assessments

Must give written informed consent to participate in this study before the performance of any study-related procedure

Exclusion Criteria:

A primary lymphoma of the central nervous system (CNS) or known lymphomatous involvement of the CNS

Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of CPI-1205, including any unresolved nausea, vomiting, or diarrhea that is CTCAE grade >1

Treatment with proton pump inhibitors, H2 antagonists, or antacids

Achlorhydria, either documented or suspected on the basis of an associated disease (e.g., pernicious anemia, atrophic gastritis, or certain gastric surgical procedures)

Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

• Acute myocardial infarction or angina pectoris ≤ 6 months prior to starting study drug
• New York Heart Association Class III or IV congestive heart failure
• QTcF > 470 msec on the screening ECG

Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded)

A past medical history of other clinically significant cardiovascular disease (e.g., uncontrolled hypertension, history of labile hypertension or history of poor compliance with an antihypertensive regimen)

Any other concurrent severe and/or uncontrolled concomitant medical condition that could compromise participation in the study (e.g., clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection)

Systemic anti-cancer treatment or radiotherapy less than 2 weeks before the first dose of CPI 1205

Radioimmunotherapy (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan) less than 6 weeks before the first dose of CPI-1205

Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-1205.

Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-1205.

Treatment with medications that are strong inhibitors of CYP3A4

Treatment with medications that are inducers of CYP3A4 enzymes

Treatment with medications that are known to carry a risk of Torsades de Pointes

Pregnant or lactating women

Women of child bearing potential and men with reproductive potential, if they are unwilling to use adequate contraception while on study therapy and for 3 months thereafter

Patients unwilling or unable to comply with this study protocol

Contacts and Locations

Locations

United States, Indiana

Horizon Oncology Center

Lafayette, Indiana, United States, 47905

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

United States, Nebraska

University of Nebraska Medical Center

Omaha, Nebraska, United States, 68198

United States, New Jersey

John Theurer Cancer Center

Hackensack, New Jersey, United States, 07601

United States, Ohio

The Ohio State University James Cancer Hospital

Columbus, Ohio, United States, 43210

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

Sponsors and Collaborators

Constellation Pharmaceuticals

Investigators

• Study Director: Debbie Johnson; Constellation Pharmaceuticals

More Information

• Responsible Party: Constellation Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02395601
• Other Study ID Numbers: 1205-01
• First Posted: March 23, 2015
• Last Update Posted: September 6, 2019
• Last Verified: September 2019

Keywords provided by Constellation Pharmaceuticals:

B-Cell Lymphoma; EZH2 Inhibitor; Phase 1

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action