A Phase 1b/2 Study of the ROR1-Targeting Monoclonal Antibody, Cirmtuzumab (UC-961), and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With B-Cell Lymphoid Malignancies
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Oncternal Therapeutics, Inc
- Enrollment
- 95
- Locations
- 12
- Primary Endpoint
- Overall Response
Overview
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.
Detailed Description
This is a Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab (INN:zilovertamab), 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), previously treated mantle cell lymphoma (MCL) subjects that are BTKI naiive or have received a prior Bruton tyrosine kinase (BTK) inhibitor therapy, unless they demonstrated primary or acquired resistance to BTKi. Up to 48 subjects will be enrolled in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up to 60 subjects (CLL/SLL, MCL and MZL (marginal zone lymphoma) 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. MZL subjects that have been previously treated and have relapsed after or progressed during at least one prior anti-CD20 -based therapy will be evaluated. In the Phase 2 (Part 3) portion of the study, approximately 30 subjects with CLL/SLL who may have received minimal prior BTK inhibitor therapy 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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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 \[Grade 1 or Grade 2 permitted with exceptions as noted below\]).
Exclusion Criteria
- •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.
Arms & Interventions
Part 1
Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Intervention: Cirmtuzumab (2-16 kg/mg) plus Ibrutinib (Drug)
Part 1
Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Intervention: Cirmtuzumab (300mg) plus Ibrutinib (Drug)
Part 1
Cirmtuzumab followed by Cirmtuzumab plus ibrutinib
Intervention: Cirmtuzumab (600 mg) plus ibrutinib (Drug)
Part 2
Cirmtuzumab plus ibrutinib
Intervention: Cirmtuzumab (RDR) plus ibrutinib (Drug)
Part 3 - Arm A
Cirmtuzumab plus ibrutinib
Intervention: Cirmtuzumab plus ibrutinib (Drug)
Part 3 - Arm B
Ibrutinib only
Intervention: Ibrutinib alone (Drug)
Outcomes
Primary Outcomes
Overall Response
Time Frame: up to 5 years
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 \[Cheson 2014\].
Secondary Outcomes
- 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)