Chronic Lymphocytic Leukemia
Conditions
Keywords
CLL, cancer, UC-961, cirmtuzumab
Brief summary
The purpose of the study is to investigate the safety of the investigational drug called cirmtuzumab when given for a duration of 6 to 12 months. Cirmtuzumab is a type of drug called a monoclonal antibody. This drug is designed to attach to a protein called ROR1 that is on the surface of chronic lymphocytic leukemia (CLL) cells. This blocks growth and survival of the CLL cells. ROR1 is rarely expressed on healthy cells so this drug should target the cancer cells. Cirmtuzumab is considered experimental because its use is not approved by United States (US) Food and Drug Administration (FDA). Although there is evidence from tests on laboratory animals that cirmtuzumab can decrease the number of CLL cells, the investigators do not know if this will work in humans. Therefore, the goal of this study is to see if cirmtuzumab is safe and tolerable in study participants when given for a duration of 6 to 12 months.
Detailed description
This is an open-label extension study to determine the safety and tolerability of cirmtuzumab given to participants who enrolled and completed the initial phase 1 trial in CLL without a dose-limiting toxicity. UC-961 is administered by intravenous infusion every 14 days for 4 doses, then every 28 days for 4 doses, after which responses will be assessed. Patients with an objective response (meeting working group criteria for partial response or complete response) will continue at the same dose and schema. Patients with stable disease or progressive disease are eligible to increase the dose of UC-961 for another 6-month course. Duration of UC-961 administration is until disease progression, treatment intolerance, or lack of clinical benefit.
Interventions
DRUGcirmtuzumab
Sponsors
University of California, San Diego
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
* Clinical and phenotypic verification of B cell CLL and measurable disease. Immunophenotyping of the leukemic cells (blood or marrow) must demonstrate a monoclonal (or light chain positive) B cell population with immunophenotype consistent with CLL (e.g., co-expressing CD19 and CD5). * Recovered from toxic effects attributed to UC-961 to grade 1 levels, or baseline. * Must have measurable disease, including one of the following: * absolute lymphocyte count greater than 5000/microliter * lymphadenopathy greater than 1.5 cm in longest dimension * splenomegaly * bone marrow biopsy with residual CLL cells, or resultant bone marrow dysfunction * Women of childbearing potential must agree not to become pregnant for the duration of the study. Both men and women must agree to use a barrier method of contraception for the duration of the study and until 10 weeks after the final dose of UC-961. * Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Adequate hematologic function * Adequate renal function * Adequate hepatic function * Adequate coagulation tests
Exclusion criteria
* Pregnant or breast-feeding women * May have had intervening therapy since completion of initial UC-961 dosing, but excluding the following: * Within 7 days of UC-961 restart, or 5 half-lives (if known), whichever is shorter: small molecule tyrosine kinase inhibitor (eg: ibrutinib, idelalisib, AVL-292, IPI-145); * Within 28 days of UC-961 restart: chemotherapy (e.g., purine analogues, alkylating agents), corticosteroids, radiation therapy, or participation in any other investigational drug treatment (besides UC-961); * Within 56 days of UC-961 restart: previous UC-961 dosing; * Within 56 days of UC-961 restart: monoclonal antibody therapy directed against CLL (e.g., rituximab, ofatumumab, obinutuzumab, alemtuzumab). * Current infection requiring parenteral antibiotics. * Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). * Concurrent malignancy or prior malignancy within the previous 3 years (other than completely resected carcinoma in situ, prostate cancer, or localized non-melanoma skin cancer). * Known central nervous system (CNS) involvement by malignancy. * Untreated autoimmunity such as autoimmune hemolytic anemia, or immune thrombocytopenia. * Uncompensated hypothyroidism (defined as thyroid stimulating hormone greater than 2x upper limit of normal not treated with replacement hormone). * Presence of more than 55% pro-lymphocytes in peripheral blood. Patients with Richter's transformation are not excluded. * Insufficient recovery from surgical-related trauma or wound healing. * Impaired cardiac function including any of the following: * Myocardial infarction within 6 months of starting study drug; * A past medical history of clinically significant electrocardiogram (ECG) abnormalities; * Other clinically significant heart disease (e.g. uncontrolled congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | From start of investigational treatment to discontinuation from trial participation, on average 159 days | Adverse events (AE) assessed by CTCAE v4.0 during cirmtuzumab treatment and during 3 months of follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From start of investigational treatment to discontinuation from trial participation, on average 159 days | Overall response rate by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria following 6 months of biweekly dosing of cirmtuzumab |
| Progression Free Survival (PFS) | From start of investigational treatment to tumor progression or death, on average 16.66 months | The duration of time from the start of study treatment until objective tumor progression or death determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria |
| Stable Disease Rate (SD) | From start of investigational treatment to discontinuation from trial participation, on average 159 days | The Stable Disease Rate based on number of subjects who have absence of disease progression as determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. |
| Partial Response Rate (PR) | From start of investigational treatment to discontinuation from trial participation, on average 159 days | The percentage of subjects who achieve partial clinical response determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. |
| Undetectable Minimal Residual Disease (uMRD) Rate | From start of investigational treatment to discontinuation from trial participation, on average 159 days | The Undetectable Minimal Residual Disease rate based on the number of subjects achieving undetectable minimal residual disease as determined by International Workshop on Chronic Lymphocytic Leukemia (iWCLL) criteria. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cirmtuzumab Cirmtuzumab 16 mg/kg | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Cirmtuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 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 | 3 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0
Adverse events (AE) assessed by CTCAE v4.0 during cirmtuzumab treatment and during 3 months of follow-up
Time frame: From start of investigational treatment to discontinuation from trial participation, on average 159 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Thrombocytopenia | 7 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Skin and subcutaneous tissue disorders, other | 1 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Eye disorders | 1 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Upper respiratory infection | 0 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Constipation | 0 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Anemia | 5 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Abdominal pain | 1 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Generalized muscle weakness | 1 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Dizziness | 2 Adverse Events |
| Grade 1 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Gastrointestinal disorders, other | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Dizziness | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Skin and subcutaneous tissue disorders, other | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Gastrointestinal disorders, other | 1 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Thrombocytopenia | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Eye disorders | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Anemia | 1 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Constipation | 1 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Upper respiratory infection | 1 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Abdominal pain | 0 Adverse Events |
| Grade 2 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Generalized muscle weakness | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Abdominal pain | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Constipation | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Gastrointestinal disorders, other | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Dizziness | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Upper respiratory infection | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Generalized muscle weakness | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Skin and subcutaneous tissue disorders, other | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Thrombocytopenia | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Anemia | 0 Adverse Events |
| Grade 3 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Eye disorders | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Generalized muscle weakness | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Constipation | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Anemia | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Upper respiratory infection | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Dizziness | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Gastrointestinal disorders, other | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Abdominal pain | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Eye disorders | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Thrombocytopenia | 0 Adverse Events |
| Grade 4 Adverse Events | Number of Treatment-emergent Adverse Events as Assessed by CTCAE v4.0 | Skin and subcutaneous tissue disorders, other | 0 Adverse Events |
Secondary
Overall Response Rate
Overall response rate by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria following 6 months of biweekly dosing of cirmtuzumab
Time frame: From start of investigational treatment to discontinuation from trial participation, on average 159 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade 1 Adverse Events | Overall Response Rate | 0 percentage of participants |
Secondary
Partial Response Rate (PR)
The percentage of subjects who achieve partial clinical response determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.
Time frame: From start of investigational treatment to discontinuation from trial participation, on average 159 days
Population: All 3 patients has stable disease while on treatment. Partial response rate is therefore 0%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade 1 Adverse Events | Partial Response Rate (PR) | 0 percentage of participants |
Secondary
Progression Free Survival (PFS)
The duration of time from the start of study treatment until objective tumor progression or death determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
Time frame: From start of investigational treatment to tumor progression or death, on average 16.66 months
Population: Only one subject progressed after being on study at 16.66 months. The other two subjects did not progress but went off study at months 3.84 and 1.26, respectively; thus, their PFS status was censored at off study date.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Grade 1 Adverse Events | Progression Free Survival (PFS) | 16.66 months | Standard Deviation 0 |
Secondary
Stable Disease Rate (SD)
The Stable Disease Rate based on number of subjects who have absence of disease progression as determined by International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.
Time frame: From start of investigational treatment to discontinuation from trial participation, on average 159 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade 1 Adverse Events | Stable Disease Rate (SD) | 100 percentage of participants |
Secondary
Undetectable Minimal Residual Disease (uMRD) Rate
The Undetectable Minimal Residual Disease rate based on the number of subjects achieving undetectable minimal residual disease as determined by International Workshop on Chronic Lymphocytic Leukemia (iWCLL) criteria.
Time frame: From start of investigational treatment to discontinuation from trial participation, on average 159 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Grade 1 Adverse Events | Undetectable Minimal Residual Disease (uMRD) Rate | 0 percentage of participants |