Lymphoma, Relapsed and Refractory, Diffuse Large B-Cell Lymphoma and Follicular Lymphoma
Conditions
Keywords
Mocetinostat, 14-106
Brief summary
The purpose of this study is to learn if the study drug mocetinostat can slow the progression of cancer in people who have a mutation in CREBBP or EP300 in the genetic makeup of their cancer. The potential side effects of mocetinostat will also be studied.
Interventions
DRUGMocetinostat
Sponsors
MethylGene Inc.
Memorial Sloan Kettering Cancer Center
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
* Patient has provided a signed study Informed Consent Form prior to performance of any study related procedurePatient is ≥ 18 years of age * Patient has histologically confirmed diagnosis of diffuse large B cell lymphoma or follicular lymphoma harboring mutations in CREBBP or EP300 with relapsed or refractory disease * Patients with diffuse large B cell lymphoma must have received at least two prior therapies and have received, declined or be ineligible for autologous or allogeneic stem cell transplant. * Patients with follicular lymphoma must have received at least two prior therapies. * Patients with either diffuse large B cell lymphoma or follicular lymphoma will be allowed to enroll after receiving only 1 prior therapy if they are felt to not be a candidate for further systemic chemotherapy. * Patient has at least one measurable lesion (≥ 2 cm) according to Cheson criteria \[45\]. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 - Patient has adequate bone marrow and organ function by: Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9/L * Platelets ≥ 75 x 10\^9/L (no platelet transfusion within past 14 days) * Hemoglobin (Hgb) ≥ 9.0 g/dL (no RBC transfusion within past 14 days) * International Normalized Ratio (INR) ≤ 1.5 * Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within 2.5 x ULN, or ≤ 5.0 x ULN for patients with documented hepatic involvement * Serum bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for patients with Gilbert Syndrome or documented hepatic involvement. * Patients must have fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy (residual grade 1 toxicity, e.g. grade 1 peripheral neuropathy, and residual alopecia are allowed)
Exclusion criteria
* Patient has received previous treatment with HDAC inhibitors * Patient has evidence of graft versus host disease (GVHD) * Patient has active or history of central nervous system (CNS) disease * Patient has impaired cardiac function including any of the following: * Presence or history of pericardial effusion (definitions are provided in and/or pericarditis. * Acute myocardial infarction, symptomatic angina pectoris ≤ 6 months prior to starting study drug * Presence of congestive heart failure ≥ NYHA class 3 * QTc \> 480 ms on a screening ECG * Screening LVEF \< 45% by echocardiography or MUGA * Uncontrolled cardiac arrhythmia including uncontrolled atrial fibrillation/atrial flutter/sinus tachycardia, complete left bundle branch block, congenital long QT syndrome * Presence of permanent cardiac pacemaker * Other clinically significant heart disease * Subject is taking warfarin at start of treatment or within 6 months prior to start of study treatment. * Patient has a concurrent malignancy or has a malignancy within 3 years of study enrollment (with the exception of adequately treated basal or squamous cell carcinoma or nonmelanomatous skin cancer) * Patient is concurrently using other approved or investigational antineoplastic agent * Patient has received chemotherapy, targeted anticancer therapy, pelvic and/or para-aortic radiotherapy or has had major surgery ≤ 4 weeks (6 weeks for nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy * Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of mocetinostat (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) * Patient is currently receiving increasing or chronic treatment (\> 10 days) with corticosteroids or another immunosuppressive agent. The following uses of corticosteroids are permitted: single dose, topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular). * Patient has a history of non-compliance to medical regimen or inability to grant consent. * Concomitant medications causing prolonged QT which cannot be discontinued or changed to a different medication prior to initiating study * Patient is currently being treated with drugs known to be moderate or strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Patients must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the start of treatment. Note: the oral anti-diabetic drugs troglitazone and pioglitazone are CYP3A inducers. * Patient has a known history of HIV (testing not mandatory), active Hepatitis B or C infection. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test (\> 5 mIU/mL) * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy as Defined by Overall Response | 1 year | as defined by overall response rate of Mocetinostat at one year in patients with relapsed/refractory DLBCL and FL who have inactivating mutations of acetyltransferase genes. Response will be measured according to the 2007 revised Cheson criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in sum of the product of the diameters (SPD) of up to 6 dominant lesions identified at baseline; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | up to 17.8 months | defined as time from the date of treatment start to the date of the first documented progressive disease (PD) or death due to any cause) rate using mocetinostat in this selected population will be estimated by the Kaplan-Meier method. Relapsed disease/progressive disease is defined as at least 50% increase of target measurable nodal lesions |
| Median Progression Free Survival/PFS | up to 17.8 months | is defined as the time from the date of first occurrence of CR or PR whichever is recorded first to the date of the first objectively documented progressive disease (PD) or death due to any cause. The duration of response will be assessed based on the sub-cohort of patients who showed responses also using Kaplan-Meier. |
| Number of Participants Evaluated for Toxicity According to the (NCI CTCAE) Version 4.0. | 2 years | will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mocetinostat Participants who harbor mutations for CREBBP and/or EP300 will be started on mocetinostat. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Nonevaluable | 1 |
Baseline characteristics
| Characteristic | Mocetinostat |
|---|---|
| Age, Continuous | 67 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 7 |
| other Total, other adverse events | 6 / 7 |
| serious Total, serious adverse events | 1 / 7 |
Outcome results
Primary
Efficacy as Defined by Overall Response
as defined by overall response rate of Mocetinostat at one year in patients with relapsed/refractory DLBCL and FL who have inactivating mutations of acetyltransferase genes. Response will be measured according to the 2007 revised Cheson criteria for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in sum of the product of the diameters (SPD) of up to 6 dominant lesions identified at baseline; Overall Response (OR) = CR + PR.
Time frame: 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mocetinostat | Efficacy as Defined by Overall Response | Partial Response | 1 Participants |
| Mocetinostat | Efficacy as Defined by Overall Response | Stable Disease | 3 Participants |
| Mocetinostat | Efficacy as Defined by Overall Response | Progression of Disease | 2 Participants |
| Mocetinostat | Efficacy as Defined by Overall Response | Not Evaluable | 1 Participants |
Secondary
Event Free Survival
defined as time from the date of treatment start to the date of the first documented progressive disease (PD) or death due to any cause) rate using mocetinostat in this selected population will be estimated by the Kaplan-Meier method. Relapsed disease/progressive disease is defined as at least 50% increase of target measurable nodal lesions
Time frame: up to 17.8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mocetinostat | Event Free Survival | 4.6 months |
Secondary
Median Progression Free Survival/PFS
is defined as the time from the date of first occurrence of CR or PR whichever is recorded first to the date of the first objectively documented progressive disease (PD) or death due to any cause. The duration of response will be assessed based on the sub-cohort of patients who showed responses also using Kaplan-Meier.
Time frame: up to 17.8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mocetinostat | Median Progression Free Survival/PFS | 4.6 months |
Secondary
Number of Participants Evaluated for Toxicity According to the (NCI CTCAE) Version 4.0.
will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Mocetinostat | Number of Participants Evaluated for Toxicity According to the (NCI CTCAE) Version 4.0. | 7 Participants |