Advanced Adult Hepatocellular Carcinoma, Advanced Fibrolamellar Carcinoma
Conditions
Keywords
Advanced Fibrolamellar Carcinoma
Brief summary
The purpose of the study is to determine whether once-daily dosing with ENMD-2076 will be a safe and effective treatment in patients with FLC. Safety will be measured by looking at the adverse events that may happen and the efficacy will look at the progression of the disease over time.
Detailed description
Primary Objective: • To determine the 6-month progression free survival (PFS6) rate when patients with advanced fibrolamellar carcinoma (FLC) are treated with daily oral ENMD 2076 Secondary Objectives: * To evaluate the overall response rate using RECIST v 1.1 criteria when patients with FLC are treated with daily oral ENMD 2076. * To evaluate the median Progression Free Survival (PFS), Time to Progression (TTP), and Overall Survival (OS). * To determine the safety of ENMD-2076 as defined by the frequency and severity of adverse events when patients with FLC are treated with daily oral ENMD-2076
Interventions
DRUGENMD-2076
250 mg oral dose, once daily (QD) for 28 day cycles
Sponsors
CASI Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed advanced fibrolamellar carcinoma (FLC). * All forms of prior local therapy are allowed as long as patients have either a target lesion, which has not been treated with local therapy and/or the target lesion(s) within the field of the local-regional therapy has shown an increase of ≥ 20% in size. Local-regional therapy must be completed at least 4 weeks prior to the baseline CT scan. Local therapies including chemoembolization do not count as prior systemic therapy. * Are at least 4 weeks from major surgery and recovered. * At least one measureable lesion by RECIST 1.1. * Male or non-pregnant, non-breastfeeding female at least 18 years of age. Patients aged at 12\ 18 years may be recruited but only at the site principle investigator's request and subject to Institutional Review Board (IRB) approval. * Has a pre-study echocardiogram or multi-gated acquisition (MUGA) scan with an actual left ventricular ejection fraction of greater than or equal to the institutional lower limit of normal within one month of initiating therapy. * Have clinically acceptable laboratory screening results within certain limits specified below: * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 times upper limit of normal (ULN) * Total bilirubin ≤ 3.0 x ULN * Creatinine ≤ 1.5 x ULN or Cr Cl \> 60 cc/min * Absolute neutrophil count ≥ 1500 cells/mm3 * Platelets ≥ 50,000/mm3 * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 for ≥ 16 years of age and a Lansky performance status of 70-100 for \< 16 years of age * Women and men of child producing potential must agree to use effective contraceptive methods prior to study entry, during study participation, and for at least 30 days after the last administration of study medication. A serum pregnancy test within 72 hours prior to the initiation of therapy will be required for women of childbearing potential. * Have the ability to understand the requirements of the study, provide written informed consent, which includes authorization for release of protected health information, abide by the study restrictions, and agree to return for the required assessments.
Exclusion criteria
* Have active, acute, or chronic clinically significant infections or bleeding within the last 6 months or previous thromboembolic or hemorrhagic events during anti angiogenic therapy. * Have uncontrolled hypertension (systolic blood pressure greater than 150 or diastolic blood pressure greater than 100) or history of congestive heart failure (AHA Grade 2 or higher). * Have active angina pectoris, stroke or recent myocardial infarction (within 6 months). * Have uncontrolled chronic atrial fibrillation. * Have chronic atrial fibrillation or QTc interval corrected for heart rate of greater than 470 msec in adults and 450 msec in pediatrics (\< 18 years). * Have additional uncontrolled serious medical or psychiatric illness that in the point of view of the investigator can render the patient unable to receive therapy or make it unsafe to receive therapy. * Require treatment with any of the exclusionary medications listed in Appendix D. * Known untreated or unstable central nervous system (CNS) metastatic disease. * Have persistent 2+ protein by urinalysis (patients with 2+ proteinuria that have a spot protein:creatinine ratio of less than 0.3 may be enrolled) or a history of nephrotic syndrome. * Subjects with history of another primary cancer, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the investigator will not affect patient outcome in the setting of current FLC diagnosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | 6 months | 6-month overall response rate (ORR rate) using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR) - disappearance of all target lesions; partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; ORR = proportion of patients evaluated as CR + PR |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 6 months | using RECIST v 1.1 criteria |
Other
| Measure | Time frame | Description |
|---|---|---|
| Frequency and Severity of Adverse Events | 6 months | Frequency and severity of adverse events in patients evaluable for toxicity |
Countries
United States
Participant flow
Pre-assignment details
43 patients screened; 35 patients enrolled
Participants by arm
| Arm | Count |
|---|---|
| ENMD-2076 ENMD-2076, oral capsule Once daily dose 250 mg/day 28 day cycles | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | ENMD-2076 | — |
|---|---|---|
| Age, Continuous | 25 years | — |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 0: Fully active, able to carry on all pre-disease performance without restriction | 12 participants | — |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 1: Restricted in physically strenuous activity but ambulatory, able do work of a light nature | 19 participants | — |
| Eastern Cooperative Oncology Group (ECOG) status ECOG 2: Ambulatory and capable of selfcare, unable to carry out any work; up >50% of waking hours | 2 participants | — |
| Lansky status Lansky 100: Fully active | 1 participants | — |
| Lansky status Lansky 90: Minor restriction in physically strenuous play | 1 participants | — |
| Number of prior systemic therapies | 4 Number of prior systemic therapies | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 19 Participants | — |
| Sex: Female, Male Male | 16 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 35 |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 4 / 35 |
Outcome results
Primary
Overall Response Rate
6-month overall response rate (ORR rate) using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR) - disappearance of all target lesions; partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; ORR = proportion of patients evaluated as CR + PR
Time frame: 6 months
Population: Patients treated and evaluable for efficacy
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ENMD-2076 | Overall Response Rate | Partial response | 1 Participants |
| ENMD-2076 | Overall Response Rate | Stable disease | 20 Participants |
| ENMD-2076 | Overall Response Rate | Progressive disease | 10 Participants |
| ENMD-2076 | Overall Response Rate | Other / unknown | 4 Participants |
Secondary
Progression Free Survival
using RECIST v 1.1 criteria
Time frame: 6 months
Population: patients treated and evaluable for efficacy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ENMD-2076 | Progression Free Survival | 3.9 months |
Other Pre-specified
Frequency and Severity of Adverse Events
Frequency and severity of adverse events in patients evaluable for toxicity
Time frame: 6 months
Population: patients treated and evaluable for toxicity assessment; regardless of relationship to study medication according to CTCAE 5.0
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ENMD-2076 | Frequency and Severity of Adverse Events | Fatigue | 27 Participants |
| ENMD-2076 | Frequency and Severity of Adverse Events | ALT increased | 26 Participants |
| ENMD-2076 | Frequency and Severity of Adverse Events | AST increased | 24 Participants |
| ENMD-2076 | Frequency and Severity of Adverse Events | Abdominal pain | 23 Participants |
| ENMD-2076 | Frequency and Severity of Adverse Events | Diarrhea | 23 Participants |