Lymphoma
Conditions
Keywords
Phase 1, Oncology, BET Inhibitor
Brief summary
First in human, open-label, sequential dose escalation and expansion study of CPI-0610 in patients with progressive lymphoma. CPI-0610 is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins.
Interventions
DRUGCPI-0610
Sponsors
The Leukemia and Lymphoma Society
Constellation Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults (aged ≥ 18 years) * Histologically confirmed diagnosis of a non-Hodgkin or Hodgkin lymphoma that has progressed in spite of prior treatment, and for which additional effective standard therapy is not available * Patients may have either measurable or non-measurable disease, but in all cases eligible patients must have disease that can be clinically evaluated for improvement or progression * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 * Adequate hematological, renal, hepatic, and coagulation laboratory assessments * 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. CNS imaging and cerebrospinal fluid sampling are not mandatory in the absence of a clinical suspicion of lymphomatous involvement of the CNS. * Current infection with HIV, Hepatitis B or Hepatitis C. Patients will have serologic testing performed during screening for HIV and Hepatitis B and C. Any serologic results suggestive of an ongoing viral infection will be further investigated as necessary to clarify the patient's status. * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of CPI-0610, including any unresolved nausea, vomiting, or diarrhea that is CTCAE grade \>1. * 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 * Serum cardiac troponin (cTn) level ≥ 99% percentile of the upper reference limit * QTcF \> 470 msec on the screening ECG * Left ventricular ejection fraction (LVEF) \< 40% * Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial fibrillation are not excluded.) * 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-0610 * Radioimmunotherapy (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan) less than 6 weeks before the first dose of CPI-0610 * Treatment with an investigational small molecule less than 2 weeks before the first dose of CPI-0610. In addition, the first dose of CPI-0610 should not occur before a period equal to or greater than 5 half-lives of the small molecule investigational agent has elapsed. * Treatment with a therapeutic antibody less than 4 weeks before the first dose of CPI-0610. A minimum 2-week period between the last treatment with a therapeutic antibody and the first dose of CPI-0610 may be permitted in patients with rapidly progressive or aggressive subtypes of lymphoma following discussion with the medical monitor. * Treatment with medications that are known to be strong inhibitors or inducers of CYP450 enzymes. * Treatment with medications that are known to carry a risk of Torsades de Pointes. * Immunosuppressive treatment that cannot be discontinued both prior to study entry and for the duration of the study. Oral prednisone at a dose of 10 mg or less per day is allowed, as are other oral corticosteroids given at glucocorticoid-equivalent doses. Topical, nasal and inhaled corticosteroids are also allowed. * 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Frequency of dose-limiting toxicities (DLTs) associated with CPI-0610 administration during the first cycle (first 21 days) of treatment | DLTs asessed during Cycle 1 (first 21 days on study) |
Secondary
| Measure | Time frame |
|---|---|
| Safety and tolerability of CPI-0610 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, ECHO and ECOG score | Assessed from Day 1 of Cycle 1 through 30 days after patient's last dose of study drug |
| Pharmacokinetic parameters of CPI-0610: AUC(0-t), AUC(0-inf), AUCtau,ss, Tmax, Cmax, Ctrough, T1/2, Vd/F, CL/F | Assessed during cycle 1 (first 21 days on study); and on cycle 2, day 1 |
| Pharmacodynamic effects of CPI-0610: Changes in the expression of MYC and other genes in tumor tissue; changes in cellular proliferation and in the extent of apoptosis; changes in tumor metabolism | Assessed during cycle 1 (first 21 days on study); and on cycle 2, day 1 |
| Changes in the expression of a set of genes in peripheral blood mononuclear cells (PBMCs) that are sensitive to BET inhibition | Assessed during cycle 1 (first 21 days on study) |
| Anti-lymphoma activity associated with CPI-0610 treatment | After every 2 cycles of treatment for the first 6 cycles, and after every 4 cycles thereafter; assessed up to approximately 12 months |
Outcome results
None listed