UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

NCT02222688 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: #140141
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Lymphocytic Leukemia

Keywords

cancer; CLL

Outcome Measures

Primary Outcomes (2)

• 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.

  1 year

• 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.

  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

Secondary Outcomes (3)

• 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

• 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

• Progression Free Survival as Determined by iwCLL Criteria

  From start of treatment until objective tumor progression or death

Study Arms (7)

Cirmtuzumab 0.015 - 0.03 mg/kg

EXPERIMENTAL

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

Drug: cirmtuzumab

Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg

EXPERIMENTAL

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

Drug: cirmtuzumab

Cirmtuzumab 0.5 - 1.0 mg/kg

EXPERIMENTAL

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

Drug: cirmtuzumab

Cirmtuzumab 2.0 - 4.0 mg/kg

EXPERIMENTAL

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

Drug: cirmtuzumab

Cirmtuzumab 8 mg/kg

EXPERIMENTAL

Cohort 5: Cirmtuzumab 8 mg/kg for four 14-day cycles via IV infusion

Drug: cirmtuzumab

Cirmtuzumab 16 mg/kg

EXPERIMENTAL

Cohort 6: Cirmtuzumab 16 mg/kg for four 14-day cycles (or maximum 2000 mg) via IV infusion

Drug: cirmtuzumab

Cirmtuzumab 20 mg/kg

EXPERIMENTAL

Cohort 7: Cirmtuzumab 20 mg/kg for four 14-day cycles (or maximum 2000 mg)

Drug: cirmtuzumab

Interventions

cirmtuzumab DRUG

Also known as: UC-961

Cirmtuzumab 0.015 - 0.03 mg/kg; Cirmtuzumab 0.06 - 0.12 - 0.24 mg/kg; Cirmtuzumab 0.5 - 1.0 mg/kg; Cirmtuzumab 16 mg/kg; Cirmtuzumab 2.0 - 4.0 mg/kg; Cirmtuzumab 20 mg/kg; Cirmtuzumab 8 mg/kg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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;

Sponsors & Collaborators

• Thomas Kipps: lead

Study Sites (1)

UCSD Moores Cancer Center

La Jolla, California, 92093, United States

Location

Related Publications (1)

• Choi MY, Widhopf GF 2nd, Ghia EM, Kidwell RL, Hasan MK, Yu J, Rassenti LZ, Chen L, Chen Y, Pittman E, Pu M, Messer K, Prussak CE, Castro JE, Jamieson C, Kipps TJ. Phase I Trial: Cirmtuzumab Inhibits ROR1 Signaling and Stemness Signatures in Patients with Chronic Lymphocytic Leukemia. Cell Stem Cell. 2018 Jun 1;22(6):951-959.e3. doi: 10.1016/j.stem.2018.05.018.

  PMID: 29859176 RESULT

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms

Interventions

cirmtuzumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Some patients enrolled in extension study (#NCT02860676)\& cut-off date for AE observation may be date patient was first treated on extension, therefor AE Timeframe period difficult to reconcile. 0 deaths observed during study observation period.

Results Point of Contact

• Title: Thomas Kipps, MD, PhD
• Organization: University of California, San Diego

tkipps@ucsd.edu

858-534-5400

Study Officials

• Catriona Jamieson, M.D., Ph.D.

  University of California Medical Center

  PRINCIPAL INVESTIGATOR

• Michael Choi, M.D.

  University of Calilfornia Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Deputy Director of Research Operations, Moores Cancer Center

Study Record Dates

• First Submitted: August 19, 2014
• First Posted: August 21, 2014
• Study Start: August 8, 2014
• Primary Completion: October 10, 2017
• Study Completion: May 1, 2018
• Last Updated: August 13, 2020
• Results First Posted: August 13, 2020

Record last verified: 2020-07

Locations

US (1)