A Study of Cirmtuzumab and Ibrutinib in Patients With B-Cell Lymphoid Malignancies

NCT03088878 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: CIRM-0001 (CIRLL)
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 12

Brief Summary

This is Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab, when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR 1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia and lymphoma cells to grow and survive. ROR1 is rarely found on healthy cells.

Conditions

B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Mantle Cell Lymphoma; Marginal Zone Lymphoma

Keywords

Chronic lymphocytic leukemia; Small lymphocytic lymphoma; Mantle cell lymphoma; Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1); Bruton Tyrosine Kinase (BTK); Ibrutinib; Marginal zone lymphoma

Outcome Measures

Primary Outcomes (1)

• Overall Response

  Defined as achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL, per standardized criteria \[Hallek 2008\], as recently updated \[Hallek 2018; Cheson 2012\]; and the achievement of a CR or PR for those with MCL or MZL, per based on standardized criteria \[Cheson 2007\] as recently updated \[Cheson 2014\].

  up to 5 years

Secondary Outcomes (4)

• Progression Free Survival (PFS)

  Up to 5 years

• Overall Survival

  Up to 5 years

• Duration of Response

  Up to 5 years

• Progression-free Survival (PFS) for Patients With TP53 Mutation Status

  Up to 5 years

Study Arms (4)

Part 1

EXPERIMENTAL

Cirmtuzumab followed by Cirmtuzumab plus ibrutinib

Drug: Cirmtuzumab (2-16 kg/mg) plus Ibrutinib; Drug: Cirmtuzumab (300mg) plus Ibrutinib; Drug: Cirmtuzumab (600 mg) plus ibrutinib

Part 2

EXPERIMENTAL

Cirmtuzumab plus ibrutinib

Drug: Cirmtuzumab (RDR) plus ibrutinib

Part 3 - Arm A

EXPERIMENTAL

Cirmtuzumab plus ibrutinib

Drug: Cirmtuzumab plus ibrutinib

Part 3 - Arm B

ACTIVE COMPARATOR

Ibrutinib only

Drug: Ibrutinib alone

Interventions

Cirmtuzumab (2-16 kg/mg) plus Ibrutinib DRUG

Participants will receive escalating doses of cirmtuzumab (2-16 mg/kg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily, starting at week 4.

Also known as: UC-961, Imbruvica

Part 1

Cirmtuzumab (300mg) plus Ibrutinib DRUG

Participants will receive cirmtuzumab (300 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.

Also known as: UC-961, Imbruvica

Part 1

Cirmtuzumab (600 mg) plus ibrutinib DRUG

Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.

Also known as: UC-961, Imbruvica

Part 1

Cirmtuzumab (RDR) plus ibrutinib DRUG

Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily

Also known as: UC-961, Imbruvica

Part 2

Cirmtuzumab plus ibrutinib DRUG

Arm A: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.

Also known as: UC-961, Imbruvica

Part 3 - Arm A

Ibrutinib alone DRUG

Arm B: Participants will receive ibrutinib (420 mg) orally once daily

Also known as: Imbruvica

Part 3 - Arm B

Eligibility Criteria

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

You may qualify if:

• Men and women of age ≥18 years.
• ECOG performance status of 0, 1, or 2
• Histological diagnosis of CLL/SLL, MCL or MZL (including splenic,nodal and extranodal subtypes) as documented in medical records (pathology reports and slides or blocks should be available for review or additional testing).
• MCL has been previously treated and has relapsed after or progressed during prior therapy. CLL/SLL may have been previously treated or are treatment naïve but now require therapy. MZL has been previously treated and has relapsed after or progressed during at least one prior anti-CD20 -based therapy
• A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator).
• Patients who have received prior BTK inhibitor therapy are eligible, unless they demonstrated primary or acquired resistance to a BTK inhibitor or experienced a serious or severe adverse event attributed to BTK inhibitor therapy.
• Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥1 non-biopsied, non-irradiated lesion that measures \>1.5 cm in the longest dimension \[LD\] and ≥1.0 cm in the longest perpendicular dimension \[LPD\] as assessed by computed tomography \[CT\] or magnetic resonance imaging \[MRI\]).
• Current medical need for therapy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease.
• Completion of all previous therapy (including any Bcl-2 or PI3K inhibitor therapy, surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week (or ≥3 half-lives of the previous drug) before the start of study therapy.
• All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before the start of study therapy (with the exceptions of alopecia, or neurotoxicity \[Grade 1 or 2 permitted\], or selected laboratory parameters \[Grade 1 or Grade 2 permitted with exceptions as noted below\]).
• Adequate bone marrow function:
• Absolute neutrophil count (ANC) ≥1.0 × 109/L.
• Platelet count ≥50 × 109/L.
• Hemoglobin ≥8.0 g/dL maintained for ≥1 week from any prior transfusion.
• Adequate hepatic profile:

You may not qualify if:

• Known histological transformation to an aggressive lymphoma (ie, Richter transformation).
• Known central nervous system malignancy.
• Presence of another cancer with disease manifestations or therapy that could adversely affect subject safety or longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results.
• Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive therapy.
• Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree atrioventricular (AV) block type II, 3rd-degree AV block, or Grade ≥2 bradycardia.
• Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs.
• Contraindication for ibrutinib use because of bleeding diathesis.
• Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy. Note: Patients with localized fungal infections of skin or nails are not precluded from participation.
• In patients with prior hematopoietic progenitor cell transplantation, evidence of ongoing graft-versus-host disease (GVHD).
• Pregnancy or breastfeeding.
• Major surgery within 4 weeks before the start of study therapy.
• Prior solid organ transplantation.
• Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy.
• Use of a moderate or strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7 days prior to the expected start of ibrutinib therapy.
• Concurrent participation in another therapeutic or imaging clinical trial.

Sponsors & Collaborators

• Oncternal Therapeutics, Inc: lead
• California Institute for Regenerative Medicine (CIRM): collaborator
• University of California, San Diego: collaborator
• Pharmacyclics LLC.: collaborator

Study Sites (12)

City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, 91010, United States

Location

Sanford Stem Cell Clinical Center at UCSD

La Jolla, California, 92093, United States

Location

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Louisiana State University Health New Orleans (NCI Community Oncology Research Program)

New Orleans, Louisiana, 70112, United States

Location

Hackensack Meridian Health, John Theurer Cancer Center

Hackensack, New Jersey, 07601, United States

Location

Northwell Health

New Hyde Park, New York, 11042, United States

Location

Manhattan Hematology Oncology Research Foundation, Inc.

New York, New York, 10016, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

The Christ Hospital Lindner Research Center

Cincinnati, Ohio, 45219, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (3)

• Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.

  PMID: 17242396 BACKGROUND

• Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.

  PMID: 25113753 BACKGROUND

• Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.

  PMID: 34398557 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone

Interventions

cirmtuzumab; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; 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; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell

Results Point of Contact

• Title: Mary Breitmeyer
• Organization: Oncternal Therapeutics

mbreitmeyer@oncternal.com

760-703-2802

Study Officials

• Michael Choi, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2017
• First Posted: March 23, 2017
• Study Start: January 3, 2018
• Primary Completion: September 25, 2024
• Study Completion: September 25, 2024
• Last Updated: February 12, 2025
• Results First Posted: February 12, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)