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

Small Lymphocytic Lymphoma Clinical Trial

Official title:

A Phase 1b-2 Study of the ROR1-Targeting Monoclonal Antibody, Cirmtuzumab, and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With B-Cell Lymphoid Malignancies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03420183
• Other study ID #: CIRM-0001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 13, 2018
• Est. completion date: December 1, 2022

Study information

• Verified date: February 2019
• Source: Oncternal Therapeutics, Inc
• Contact: Xen Ianopulos, MD, PhD
• Phone: 206-434-0133
• Email: xengia[@]oncternal.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a 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 ROR1) 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.

Description:

This is a 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. The Phase 1b will be conducted in two parts (Part 1 and Part 2). Part 1 is a dose-finding evaluation of the sequential administration of cirmtuzumab monotherapy followed by cirmtuzumab and ibrutinib combination therapy in chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) or or previously treated mantle cell lymphoma (MCL) subjects who have not received prior Bruton tyrosine kinase (BTK) inhibitor therapy. Up to 48 subjects will be enrolled in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up to 18 subjects will be enrolled to further evaluate the safety and pharmacology of the cirmtuzumab and ibrutinib combination given at the RDR determined in Part 1 of the study. In the Phase 2 (Part 3) portion of the study, approximately 90 subjects with CLL will be randomized to either Arm 1 (cirmtuzumab and ibrutinib) at the RDR or Arm 2 (ibrutinib alone) to evaluate the clinical activity and safety of the two arms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 156
• Est. completion date: December 1, 2022
• Est. primary completion date: April 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Men and women of age =18 years.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

3. Histological diagnosis of CLL/SLL or MCL as documented in medical records.

4. MCL has been previously treated and has relapsed after or progressed during prior therapy.

5. No history of prior BTK-inhibitor-containing therapy.

6. A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator).

7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of =1 non-biopsied, non-irradiated lesion that measures =2.0 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]).

8. Current medical need for therapy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease.

9. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer =1 week before the start of study therapy.

10. All acute toxic effects of any prior antitumor therapy resolved to =Grade 1 before the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], or neurotoxicity [Grade 1 or 2 permitted], or selected laboratory parameters [Grade 1 or Grade 2 permitted with exceptions as noted below]).

11. Adequate bone marrow function:

1. Absolute neutrophil count (ANC) =1.0 × 10^9/L (Grade =2).

2. Platelet count =50 × 10^9/L (Grade =2).

3. Hemoglobin =8.0 g/dL (Grade =2) maintained for =1 week from any prior transfusion.

Note: Grade =3 neutropenia, thrombocytopenia, or anemia is permitted if the abnormality is related to bone marrow involvement with hematological malignancy (as documented by bone marrow biopsy/aspirate obtained since the last prior therapy).

12. Adequate hepatic profile:

1. Serum alanine aminotransferase (ALT) =3 × upper limit of normal (ULN) (Grade =1).

2. Serum aspartate aminotransferase (AST) =3 × ULN (Grade =1).

3. Serum bilirubin =1.5 × ULN (Grade = 1).

13. Adequate renal function:

1. Estimated creatinine clearance (eClCR) >45 mL/min (with eCLCR to be calculated by the Cockcroft-Gault formula, or

2. Measured creatinine clearance >45 mL/minute (as assessed with a 24-hour urine collection)

14. Adequate coagulation profile:

1. Prothrombin time (PT) =1.5 × ULN (Grade =1).

2. Activated partial thromboplastin time (aPTT) =1.5 × ULN (Grade =1).

15. Negative viral serology:

1. Negative human immunodeficiency virus (HIV) antibody.

2. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) testing.

3. Negative hepatitis C virus (HCV) antibody or negative HCV ribonucleic acid (RNA) by quantitative PCR.

16. For female subjects of childbearing potential, a negative urine or serum pregnancy test prior to the start of study therapy.

17. For female subjects of childbearing potential, willingness to use an effective method of contraception from the start of the screening period until =3 months after the last dose of cirmtuzumab and =1 month after the last dose of ibrutinib, whichever is later. Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin [beta HCG]); or is menopausal (age =50 years with amenorrhea for =6 months).

18. For male subjects who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception, willingness to use an effective method of contraception from the start of study therapy until =3 months after the last dose of cirmtuzumab and =1 month after the last dose of ibrutinib, whichever is later and to refrain from sperm donation from the start of study therapy until =3 months after administration of the final dose of either of the study drugs. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.

19. In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject's cancer.

20. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures (including all bone marrow biopsy/aspirations and radiographic studies), and study restrictions.

21. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.

Exclusion Criteria:

1. Known histological transformation to an aggressive lymphoma (ie, Richter transformation). Note: Biopsy documentation of the absence or presence of transformation is not required.

2. Known central nervous system malignancy. Note: Central nervous system imaging is only required in subjects with suspected central nervous system malignancy.

3. 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 interpetation of study results.

4. 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.

5. 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, Grade =2 bradycardia, or corrected QT (QTc) >450 msec (for men) or >470 msec (for women).

6. 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.

7. Contraindication for ibrutinib use because of a bleeding diathesis.

8. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy. Note: Subjects with localized fungal infections of skin or nails are not precluded from participation.

9. In subjects with prior hematopoietic progenitor cell transplantation, evidence of ongoing graft-versus-host disease (GVHD).

10. Pregnancy or breastfeeding.

11. Major surgery within 4 weeks before the start of study therapy.

12. Prior solid organ transplantation.

13. Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy.

14. 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.

16) Use within 7 days prior to the start of study therapy of a drug known to prolong the QT interval (study parts 1 and 2 only).

17) Concurrent participation in another therapeutic or imaging clinical trial.

18) Any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a subject's ability to provide informed consent, adversely affect the subject's ability to cooperate and participate in the study, or compromise the interpretation of study results.

Related Conditions & MeSH terms

• B-cell Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle-cell Lymphoma
• Small Lymphocytic Lymphoma

Intervention

Drug:
• Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter
• Cirmtuzumab plus ibrutinib
Cirmtuzumab: administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter Ibrutinib: Self-administered orally once daily.
• Ibrutinib
Self-administered orally once daily

Locations

Country	Name	City	State
United States	Christ Hospital Lindner Research Center	Cincinnati	Ohio
United States	City of Hope	Duarte	California
United States	MD Anderson Cancer Center	Houston	Texas
United States	MD Anderson Cancer Clinic	Houston	Texas
United States	UCSD Moores Cancer Center	La Jolla	California
United States	Manhattan Hematology Oncology of New York	Manhattan	New York
United States	Northwell Health	New Hyde Park	New York
United States	Columbia University	New York	New York

Sponsors (3)

Lead Sponsor	Collaborator
Oncternal Therapeutics, Inc	California Institute for Regenerative Medicine (CIRM), University of California, San Diego

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1b: Recommended dosing regimen (RDR)	Evaluation of cirmtuzumab dose-pharmacodynamic and pharmacokinetic-pharmacodynamic relationships, safety	From baseline to 52 weeks
Primary	Phase 2: Complete Response (CR) rate	Proportion of subjects achieving a CR in accordance with pre-established response criteria for lymphoma (Cheson 2007; Cheson 2014)	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Phase 1b: Treatment Related Adverse Events	Number of participants with adverse events and clinical laboratory abnormalities assessed by CTCAE v4.03	From baseline to 52 weeks
Secondary	Phase 2: Cirmtuzumab Serum Concentration	Concentrations measured using a validated immunoassay	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Phase 2: ROR1 Cell Surface Expression	Changes in ROR1 cell surface expression on malignant cells in peripheral blood and bone marrow.	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Phase 2: Duration of Response	The interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Phase 2: Progression Free Survival	The interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Time to Treatment Failure	The interval from the start of study therapy to the earlier of the first documentation of disease progression, the permanent cessation of study drug due to an adverse event, or death from any cause	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject
Secondary	Phase 2: Overall Survival	Defined as the interval from the start of study therapy to death from any cause	From randomization to discontinuation of treatment of all study subjects or 72 weeks after accrual of the final subject