Chronic Lymphocytic Leukemia
Conditions
Keywords
cancer, CLL
Brief summary
The purpose of the study is to investigate the safety of the investigational agent, cirmtuzumab. Cirmtuzumab is a monoclonal antibody drug designed to attach to a protein, called ROR1, on the surface of chronic lymphocytic leukemia (CLL) cells to block cell growth and survival. ROR1 is rarely expressed on healthy cells so the idea is to preferentially get rid of the cancer cells. Although there is evidence in laboratory animals that cirmtuzumab can decrease the number of CLL cells, the investigators do not know if this will work in humans. This drug will be given to humans for the first time in this study. Therefore, the goal of this study is to see if cirmtuzumab is safe and tolerated in study participants.
Detailed description
This is a first in human, open-label single institution, Phase I dose escalation study of in patients with relapsed or refractory CLL. Treatment cycle (14 days) will consist of cirmtuzumab administered intravenously on a bi-weekly (every two weeks) schedule for a total of 4 doses. Eight dose cohorts (of 3 to 6 patients in size) plus an expansion cohort of 6 patients are planned. In the first 4 dose cohorts, there is intra-patient dose escalation to monitor for acute toxicities, such as tumor lysis syndrome. A cycle may be repeated every 14 days if the patient has at least stable disease by clinical examination (or interim response assessment) and has again met hematologic, renal, and hepatic laboratory parameters as defined in the eligibility section, and is without ongoing Grade 3 non-hematologic or Grade 4 hematologic toxicities attributable to cirmtuzumab. The total duration of study drug administration is 4 cycles. Each cycle consists of clinical and laboratory evaluation on Day 1 and safety assessments on Days 3 and 8.
Interventions
DRUGcirmtuzumab
Sponsors
Thomas Kipps
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Clinical and phenotypic verification of B cell CLL and measurable disease. Immunophenotyping of the leukemic cells must demonstrate a monoclonal B cell population with immunophenotype consistent with CLL. * Relapsed or refractory disease, defined by failure to achieve a partial response within 6 months of initiation of therapy, or a 50% increase of baseline disease measurements after achieving a clinical response. * Not amenable to approved therapies. * Prior Therapy: Must have progressed after purine-analog or alkylator based therapy, or be considered inappropriate for chemo-immunotherapy due to one of the following: * Del 17p, which is associated with poor response to chemo-immunotherapy, or * Age greater than 70, or * Age greater than 65 with one of the following: * Grade ≥ 3 neutropenia, anemia, or thrombocytopenia attributable to cumulative myelotoxicity from prior administration of cytotoxic agents (as documented by bone marrow biopsy obtained since last prior therapy), or * Clinically apparent autoimmune cytopenia which may be exacerbated by fludarabine therapy, or * Estimated creatinine clearance (eCCr) \<70 mL/min (as determined by the Cockcroft-Gault method), or * Eastern Cooperative Oncology Group (ECOG) performance status greater than 0. * Has recovered from the toxic effects of prior therapy to their clinical baseline. * 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 cirmtuzumab. * Subjects must have at least one of the following indications for treatment: * Symptomatic or progressive splenomegaly; * Symptomatic lymph nodes, nodal clusters, or progressive lymphadenopathy; * Progressive anemia (hemoglobin ≤ 11 g/dL); * Progressive thrombocytopenia (platelets ≤ 100 x 10\^9/L); * Weight loss \> 10% body weight over the preceding 6 month period; * Fatigue attributable to CLL; * Fever or night sweats for \> 2 weeks without evidence of infection; * Progressive lymphocytosis with an increase of \> 50% over a 2-month period or an anticipated doubling time of less than 12 months. * Subjects must have an 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 will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. * Patients who are currently receiving another investigational agent are excluded. * Patients who have had chemotherapy (e.g., purine analogues, alkylating agents), immunotherapy, radiation therapy, or participation in any investigational drug treatment within 4 weeks of initiation of UC-961 or at any time during the study. * Patients who have had prior (within 8 weeks of initiation of UC-961) or concurrent antibody therapy directed against CLL (i.e., Rituxan® and Campath®). * Current infection requiring parenteral antibiotics. * Active infection with 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 (TSH) 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 ECG abnormalities, including QTc 481 milliseconds or greater; * Other clinically significant heart disease (e.g., 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 |
|---|---|---|
| Maximum Tolerated Dose (MTD) or Biologically Active Dose of Cirmtuzumab | 1 year | The MTD is defined as the highest dose studied at which no more than one in six patients experience a dose-limiting toxicity (DLT) during the DLT observation period. The biologically active dose will be determined at a dose below or equal to the MTD upon review of the the study data; the final determination will also consider any cumulative or delayed toxicity. |
| Rate of Dose Limiting Toxicities (DLTs) | The DLT observation period is 56 days from the start of the first infusion for the intra-patient dosing cohorts and 28 days after the start of the first infusion for subsequent dosing cohorts | The occurrence of any of the following adverse events considered to be possibly, probably, or definitely related to cirmtuzumab within the DLT observation period (56 days from the first infusion for cohorts with intrapatient dose escalation, and 28 days of the start investigational treatment for cohorts without intrapatient dose escalation): 1. Grade 3 or greater non-hematologic toxicity with the exception of Grade 3 infusion reaction. 2. Grade 4 neutropenia lasting more than 5 days despite appropriate medical management. 3. Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion. 4. Grade 3 or greater febrile neutropenia (temperature ≥ 38.5ºC). 5. Grade 4 anemia unexplained by underlying disease. 6. Any AE requiring a dose delay of greater than 14 days. 7. Patients with baseline cytopenias or starting blood counts in the grade 2 range are evaluable for hematologic DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | From the start of investigational treatment to completion of follow-up, an average of 33 weeks | Treatment emergent adverse events (description, timing, CTCAE grade, severity, seriousness, and relatedness) |
| Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | From baseline visit to response assessment visit at 56 days after final cirmtuzumab infusion, an average of 52 days | Clinical response \[stable disease (SD) or progressive disease (PD)\] defined by iwCLL criteria including clinical, hematological, and bone marrow features for a period of at least 2 months from completion of therapy |
| Progression Free Survival as Determined by iwCLL Criteria | From start of treatment until objective tumor progression or death | The duration of time from the start of study treatment until objective tumor progression or death |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled into the study between August 2014 and September 2017 and included patients seen in the UCSD Health system.
Pre-assignment details
Twenty-seven subjects were treated with cirmtuzumab and are included in the primary outcome analysis. One subject was enrolled into the trial twice; first in Cohort 1 and then again in Cohort 4 and is counted once for reporting of the baseline characteristics.
Participants by arm
| Arm | Count |
|---|---|
| Cirmtuzumab 0.015 - 0.03 mg/kg Cohort 1: Cirmtuzumab 0.015 mg/kg for two 14-day cycles followed by cirmtuzumab 0.03 mg/kg for two 14-day cycles via intravenous (IV) infusion | 4 |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg Cohort 2: Cirmtuzumab 0.06 mg/kg for one 14-day cycle, followed by cirmtuzumab 0.12 mg/kg for one 14-day cycle, followed by 0.24 mg/kg for two 14-day cycles via IV infusion | 3 |
| Cirmtuzumab 0.5 - 1.0 mg/kg Cohort 3: Cirmtuzumab 0.5 mg/kg for one 14-day cycle, followed by cirmtuzumab 1.0 mg/kg for three 14-day cycles via IV infusion | 3 |
| Cirmtuzumab 2.0 - 4.0 mg/kg Cohort 4: Cirmtuzumab 2.0 mg/kg for two 14-day cycles, followed by cirmtuzumab 4.0 mg/kg for two 14-day cycles via IV infusion | 5 |
| Cirmtuzumab 8 mg/kg Cohort 5: Cirmtuzumab 8 mg/kg for four 14-day cycles via IV infusion | 3 |
| Cirmtuzumab 16 mg/kg Cohort 6: Cirmtuzumab 16 mg/kg for four 14-day cycles (or maximum 2000 mg) via IV infusion | 3 |
| Cirmtuzumab 20 mg/kg Cohort 7: Cirmtuzumab 20 mg/kg for four 14-day cycles (or maximum 2000 mg) | 6 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Disease progression | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Cirmtuzumab 0.5 - 1.0 mg/kg | Cirmtuzumab 2.0 - 4.0 mg/kg | Cirmtuzumab 8 mg/kg | Cirmtuzumab 16 mg/kg | Cirmtuzumab 20 mg/kg | Cirmtuzumab 0.015 - 0.03 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 2 Participants | 5 Participants | 4 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Age, Continuous | 70.67 years STANDARD_DEVIATION 11.68 | 66.67 years STANDARD_DEVIATION 3.51 | 69.4 years STANDARD_DEVIATION 7.23 | 70 years STANDARD_DEVIATION 2.65 | 71.67 years STANDARD_DEVIATION 9.29 | 77.33 years STANDARD_DEVIATION 8.78 | 72.75 years STANDARD_DEVIATION 1.5 | 71.81 years STANDARD_DEVIATION 7.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 6 Participants | 4 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 2 Participants | 6 Participants | 4 Participants | 25 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 5 participants | 3 participants | 3 participants | 6 participants | 4 participants | 27 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 3 / 3 | 5 / 5 | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 3 | 0 / 5 | 0 / 3 | 1 / 3 | 2 / 6 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) or Biologically Active Dose of Cirmtuzumab
The MTD is defined as the highest dose studied at which no more than one in six patients experience a dose-limiting toxicity (DLT) during the DLT observation period. The biologically active dose will be determined at a dose below or equal to the MTD upon review of the the study data; the final determination will also consider any cumulative or delayed toxicity.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Maximum Tolerated Dose (MTD) or Biologically Active Dose of Cirmtuzumab | 20 mg/kg |
Primary
Rate of Dose Limiting Toxicities (DLTs)
The occurrence of any of the following adverse events considered to be possibly, probably, or definitely related to cirmtuzumab within the DLT observation period (56 days from the first infusion for cohorts with intrapatient dose escalation, and 28 days of the start investigational treatment for cohorts without intrapatient dose escalation): 1. Grade 3 or greater non-hematologic toxicity with the exception of Grade 3 infusion reaction. 2. Grade 4 neutropenia lasting more than 5 days despite appropriate medical management. 3. Grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion. 4. Grade 3 or greater febrile neutropenia (temperature ≥ 38.5ºC). 5. Grade 4 anemia unexplained by underlying disease. 6. Any AE requiring a dose delay of greater than 14 days. 7. Patients with baseline cytopenias or starting blood counts in the grade 2 range are evaluable for hematologic DLT.
Time frame: The DLT observation period is 56 days from the start of the first infusion for the intra-patient dosing cohorts and 28 days after the start of the first infusion for subsequent dosing cohorts
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 0.5 - 1.0 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 2.0 - 4.0 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 8 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 16 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
| Cirmtuzumab 20 mg/kg | Rate of Dose Limiting Toxicities (DLTs) | 0 Occurrence of DLTs |
Secondary
Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria
Clinical response \[stable disease (SD) or progressive disease (PD)\] defined by iwCLL criteria including clinical, hematological, and bone marrow features for a period of at least 2 months from completion of therapy
Time frame: From baseline visit to response assessment visit at 56 days after final cirmtuzumab infusion, an average of 52 days
Population: Evaluable subjects or those who completed 4 cycles of cirmtuzumab
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 0 participants |
| All Participants | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 3 participants |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 0 participants |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 3 participants |
| Cirmtuzumab 0.5 - 1.0 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 1 participants |
| Cirmtuzumab 0.5 - 1.0 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 2 participants |
| Cirmtuzumab 2.0 - 4.0 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 0 participants |
| Cirmtuzumab 2.0 - 4.0 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 3 participants |
| Cirmtuzumab 8 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 1 participants |
| Cirmtuzumab 8 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 1 participants |
| Cirmtuzumab 16 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 1 participants |
| Cirmtuzumab 16 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 2 participants |
| Cirmtuzumab 20 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Stable Disease | 2 participants |
| Cirmtuzumab 20 mg/kg | Clinical Activity Determined by the International Working Group in CLL (iwCLL) Criteria | Progressive Disease | 3 participants |
Secondary
Progression Free Survival as Determined by iwCLL Criteria
The duration of time from the start of study treatment until objective tumor progression or death
Time frame: From start of treatment until objective tumor progression or death
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Participants | Progression Free Survival as Determined by iwCLL Criteria | 29.5 Weeks |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 27.6 Weeks |
| Cirmtuzumab 0.5 - 1.0 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 24.5 Weeks |
| Cirmtuzumab 2.0 - 4.0 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 36.6 Weeks |
| Cirmtuzumab 8 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 25.4 Weeks |
| Cirmtuzumab 16 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 26.2 Weeks |
| Cirmtuzumab 20 mg/kg | Progression Free Survival as Determined by iwCLL Criteria | 19.9 Weeks |
Secondary
Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs.
Treatment emergent adverse events (description, timing, CTCAE grade, severity, seriousness, and relatedness)
Time frame: From the start of investigational treatment to completion of follow-up, an average of 33 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 20 Treatment emergent AEs |
| Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 37 Treatment emergent AEs |
| Cirmtuzumab 0.5 - 1.0 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 15 Treatment emergent AEs |
| Cirmtuzumab 2.0 - 4.0 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 31 Treatment emergent AEs |
| Cirmtuzumab 8 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 17 Treatment emergent AEs |
| Cirmtuzumab 16 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 34 Treatment emergent AEs |
| Cirmtuzumab 20 mg/kg | Safety and Tolerability of UC-961 by Ongoing Evaluation of AEs. | 46 Treatment emergent AEs |